N-of-1 medicine.

ABSTRACT: The fields of precision and personalised medicine have led to promising advances in tailoring treatment to individual patients. Examples include genome/molecular alteration-guided drug selection, single-patient gene therapy design and synergy-based drug combination development, and these approaches can yield substantially diverse recommendations. Therefore, it is important to define each domain and delineate their commonalities and differences in an effort to develop novel clinical trial designs, streamline workflow development, rethink regulatory considerations, create value in healthcare and economics assessments, and other factors. These and other segments are essential to recognise the diversity within these domains to accelerate their respective workflows towards practice-changing healthcare. To emphasise these points, this article elaborates on the concept of digital health and digital medicine-enabled N-of-1 medicine, which individualises combination regimen and dosing using a patient's own data. We will conclude with recommendations for consideration when developing novel workflows based on emerging digital-based platforms.

Addressing antimicrobial resistance with the IDentif.AI platform: Rapidly optimizing clinically actionable combination therapy regimens against nontuberculous mycobacteria.

Background: Current standard of care (SOC) regimens against nontuberculous mycobacteria (NTM) usually result in unsatisfactory therapeutic responses, primarily due to multi-drug resistance and antibiotic susceptibility-guided therapies. In the midst of rising incidences in NTM infections, strategies to develop NTM-specific treatments have been explored and validated. Methods: To provide an alternative approach to address NTM-specific treatment, IDentif.AI was harnessed to rapidly optimize and design effective combination therapy regimens against Mycobacterium abscessus (M. abscessus), the highly resistant and rapid growth species of NTM. IDentif.AI interrogated the drug interaction space from a pool of 6 antibiotics, and pinpointed multiple clinically actionable drug combinations. IDentif.AI-pinpointed actionable combinations were experimentally validated and their interactions were assessed using Bliss independence model and diagonal measurement of n-way drug interactions. Results: Notably, IDentfi.AI-designed 3- and 4-drug combinations demonstrated greater %Inhibition efficacy than the SOC regimens. The platform also pinpointed two unique drug interactions (Levofloxacin (LVX)/Rifabutin (RFB) and LVX/Meropenem (MEM)) that may serve as the backbone of potential 3- and 4-drug combinations like LVX/MEM/RFB, which exhibited 58.33±4.99 %Inhibition efficacy against M. abscessus. Further analysis of LVX/RFB via Bliss independence model pointed to dose-dependent synergistic interactions in clinically actionable concentrations. Conclusions: IDentif.AI-designed combinations may provide alternative regimen options to current SOC combinations that are often administered with Amikacin, which has been known to induce ototoxicity in patients. Furthermore, IDentif.AI pinpointed 2-drug interactions may also serve as the backbone for the development of other effective 3- and 4-drug combination therapies. The findings in this study suggest that this platform may contribute to NTM-specific drug development.

Relationship between size and location of infarction beside lateral ventricle and motor recovery following rehabilitation.

BACKGROUND: The lesions besides lateral ventricle and motor recovery following rehabilitation have hardly been studied. OBJECTIVE: To explore the relationship between the size, location of infarction beside the lateral ventricle and motor recovery following rehabilitation. METHODS: A prospective cohort of 55 patients submitted to a Rehabilitation Medical Center between January 2015 and June 2019 who suffered a single cerebral infarction beside the lateral ventricle were included in the study. The size and distance between the posterior margin and the frontal-middle line (FML) of the lesion were measured. Follow-up was conducted until the recovery was no longer progressing. Barthel index and Brunstrom stages were used to evaluate the outcome (full recovery, partial recovery and poor recovery). Variance analysis and nonparametric test were used for the comparison between groups. Multivariate logistic regression analysis was used to screen the factors affecting the outcomes. The Pearson correlation coefficient was used to compare the volume of infarction, behind the FML and the outcomes. RESULTS: Among the 55 patients, the outcome was full recovery (n = 28), partial recovery (n = 13) and poor recovery (n = 14). Multivariate logistic regression analysis showed that volume and location of the infarction were significantly correlated with the outcome (p = 0.039, 0.050). The lesion volume in the full recovery patients was significantly smaller than that in the poor recovery patients (p < 0.01). The posterior edge of the lesion in the full recovery patients behind the FML was statistically significant compared with that in the poor recovery patients (p < 0.01). Spearman correlation analysis showed that the motor recovery was negative correlation to lesion volume (r = -0.508, P < 0.01) and location (r = -0.450, P < 0.01) of the infarction. CONCLUSION: The motor recovery of patients with cerebral infarction beside lateral ventricle is related to the volume and location of the lesion. The larger the volume of the lesion, and the farther the posterior margin of the lesion to the FML, the worse the motor recovery.

IDentif.AI-Omicron: Harnessing an AI-Derived and Disease-Agnostic Platform to Pinpoint Combinatorial Therapies for Clinically Actionable Anti-SARS-CoV-2 Intervention.

Nanomedicine-based and unmodified drug interventions to address COVID-19 have evolved over the course of the pandemic as more information is gleaned and virus variants continue to emerge. For example, some early therapies (e.g., antibodies) have experienced markedly decreased efficacy. Due to a growing concern of future drug resistant variants, current drug development strategies are seeking to find effective drug combinations. In this study, we used IDentif.AI, an artificial intelligence-derived platform, to investigate the drug-drug and drug-dose interaction space of six promising experimental or currently deployed therapies at various concentrations: EIDD-1931, YH-53, nirmatrelvir, AT-511, favipiravir, and auranofin. The drugs were tested in vitro against a live B.1.1.529 (Omicron) virus first in monotherapy and then in 50 strategic combinations designed to interrogate the interaction space of 729 possible combinations. Key findings and interactions were then further explored and validated in an additional experimental round using an expanded concentration range. Overall, we found that few of the tested drugs showed moderate efficacy as monotherapies in the actionable concentration range, but combinatorial drug testing revealed significant dose-dependent drug-drug interactions, specifically between EIDD-1931 and YH-53, as well as nirmatrelvir and YH-53. Checkerboard validation analysis confirmed these synergistic interactions and also identified an interaction between EIDD-1931 and favipiravir in an expanded range. Based on the platform nature of IDentif.AI, these findings may support further explorations of the dose-dependent drug interactions between different drug classes in further pre-clinical and clinical trials as possible combinatorial therapies consisting of unmodified and nanomedicine-enabled drugs, to combat current and future COVID-19 strains and other emerging pathogens.

Successful endoscopic drainage of malignant obstructive jaundice in patients with situs inversus totalis: Two cases report.

INTRODUCTION AND IMPORTANCE: Although endoscopic techniques in situs inversus totalis (SIT) have been reported, endoscopic retrograde cholangiopancreatography (ERCP) in patients with situs inversus totalis (SIT) remains difficult to every hepatobiliary surgeon. To investigate the differences of each position, ERCP was used to perform through two different body positions. CASE PRESENTATION: Herein we report a 63-year-old woman presented with epigastric pain for 2 months and jaundice for 7 days and a 51-year-old man with presented jaundice for 7 days. Preoperative examination revealed situs inversus totalis and gallbladder carcinoma with diffuse dilatation of the biliary tree. ERCP was used to perform by using two different body positions. In addition, the ERCP combined with percutaneous transhepatic cholangial drainage (PTCD) was performed in the second patient. CLINICAL DISCUSSION: The different endoscopic approaches are used in different positions, the endoscopist should be familiar with mirror symmetrical anatomy. We argue that the prone position has a higher surgical success rate and ERCP combined with PTCD will be easier in SIT patients. CONCLUSION: ERCP in SIT patients is generally safe and it will be easier by combining with PTCD.

Usefulness of serum interleukin-33 as a prognostic marker of severe traumatic brain injury.

BACKGROUND: Interleukin-33 is recently identified as a brain injury biomarker. We determined whether serum interlerukin-33 concentrations are associated with inflammation, severity and prognosis after traumatic brain injury (TBI). METHODS: We detected serum interlerukin-33 concentrations of 102 healthy controls and 102 severe TBI patients, as well as serum concentrations of 3 inflammatory biomarkers (interleukin-6, tumor necrosis factor-alpha and C-reactive protein) and 7 cell-specific proteins (myelin basic protein, glial fibrillary astrocyte protein, S100B, neuron-specific enolase, phosphorylated axonal neurofilament subunit H, Tau and ubiquitin carboxyl-terminal hydrolase L1) in 102 severe TBI patients. The recorded poor prognosis variables included acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury, posttraumatic cerebral infarction and six-month mortality and poor outcome (Glasgow score of 1-3). RESULTS: Median interlerukin-33 concentration of patients (692 pg/mL) was substantially raised, as compared to controls. Interlerukin-33 concentrations were significantly correlated with Glasgow coma scale (GCS) score and the preceding biomarkers concentrations. Interlerukin-33 concentration > 692 pg/mL emerged as an independent prognostic predictor and its discriminatory capability exceeded those of the above-mentioned inflammatory biomarkers concentrations and was in the range of GCS scores and the aforementioned cell-specific proteins concentrations. CONCLUSION: Ascending serum interlerukin-33 concentrations could reflect inflammation, severity and worse prognosis following TBI.

Atlantoaxial Misalignment Causes High Blood Pressure in Rats: A Novel Hypertension Model.

Atlantoaxial disorders are often correlated with hypertension in practice. In order to study the relationship between atlantoaxial disorder and hypertension, we attempted to construct an animal model. In this work, we presented an animal model where their atlantoaxial joints were misaligned. We investigated the changes of blood pressure before and after treatments of the modeled rats. We had the following results. (1) SBP and DBP of each surgery group were significantly higher than those of control and sham groups. (2) After the second operation (the fixture was removed), SBP and DBP of both surgery groups decreased and got closer to the control and sham groups after 7 days. (3) Heart rates got significantly higher in both surgery groups, compared to control and sham groups. (4) The blood Ach levels of the surgery groups were significantly lower than those of control and sham groups. With these results, we concluded that we successfully constructed cervical atlantoaxial disorder models in rats that showed hypertension symptom. However, the underlying mechanism connecting atlantoaxial disorder and hypertension still requires further study.

[Transcriptome analysis of response to heavy metal Cd stress in soybean root]. / å¤§è±†æ ¹ç³»åº”ç­”é‡é‡‘å±žCd胁迫的转录组分析.

Cadmium (Cd) is a common pollutant not required for life activities, which can have extremely strong toxicity to organisms and affect the growth of crops at a low concentration in soil. To investigate the molecular mechanism of soybean root responding to Cd stress, 7-day old soybean seedlings were stressed by Cd (75 Μmol·L-1) for 0 , 4 , 8, 12 and 48 h. Comparative transcriptome analysis showed 244, 1545, 442 and 1401 of genes responded to the four Cd treatments, respectively, and total 2670 differential expression genes were obtained. GO analysis classified these genes into 56 functional categories and COG analysis classified them into 25 functional categories. KEGG analysis showed that many genes involved in the phenylalanine metabolism, ubiquinone and other terpenoid-quinone biosynthesis and cysteine and methionine metabolism and so on. Further we found that expression of three isoflavones 2'-hydroxylase genes, two isoflavonereductase genes and a chalcone synthase gene were evidently up-regulated in all Cd treatments. The results of RT-PCR analysis of four DEGs were consistent with those of RNA-Seq data, further confirming the reliability of RNA-Seq results.

Increased expression of microRNA-301a in nonsmall-cell lung cancer and its clinical significance.

AIMS: Recently, accumulating evidence indicates that dysregulation of microRNAs is associated with the initiation and progression of cancer. Oncogenic miR-301a has been reported upregulation and associated with tumorigenesis and progression in various types of cancer. The aim of this study was to investigate the expression of miR-301a in nonsmall-cell lung cancer. (NSCLC), and to assess its association with malignancy, metastasis and prognosis. SUBJECTS AND METHODS: total of 88 NSCLC patients (females = 21 and males = 67), aged 15-81 years were included in the study. miR-301a expression in tumor tissue was estimated by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: miR-301a was significantly upregulated in NSCLC tissues compared with their paired adjacent nontumor tissues. (P < 0.001). Increased expression of miR-301a was detected in tumors with lymph node metastases. (P =0.003). In addition, high miR-301a expression was significantly associated with poorly differentiation. (P =0.015), lymph node metastasis. (P =0.013) and advanced tumor-node-metastasis. (TNM) stage. (P =0.018). A. comparison of survival curves of low versus high expressers of miR-301a revealed a highly significant difference in NSCLC, which suggests that overexpression of miR-301a is associated with a poorer disease-free survival (DFS) (P =0.002). Moreover, multivariate Cox proportional hazard regression analyses revealed that the miR-301a overexpression was an unfavorable prognostic factor for disease-free survival in addition to TNM stage. CONCLUSIONS: miR-301a may represent a novel prognostic indicator, a biomarker for the early detection of lymph node metastasis and a therapeutic target in NSCLC.

Serum S100A12 levels are associated with the presence and severity of obstructive sleep apnea syndrome in male patients.

PURPOSE: Inflammation plays a critical role in the pathogenesis of obstructive sleep apnea syndrome (OSAS). S100A12 is a newly identified inflammatory biomarker. This study aims to investigate whether serum S100A12 levels are associated with the presence and severity of OSAS in male patients. METHODS: A total of 126 male patients with OSAS and 74 controls were enrolled in this study. The presence and severity of OSAS was assessed by apnea-hypopnea index (AHI). Serum S100A12 levels were detected by enzyme-linked immunosorbent assay. RESULTS: Serum S100A12 levels were significantly higher in the OSAS group than in the control group (132.17 (range 101.86 to 174.49) ng/ml vs. 78.40 (range 58.35 to 129.44) ng/ml, P < 0.01). Multivariate logistic regression demonstrated that S100A12 was the only significant and independent predictor of OSAS (odds ratio 1.012, 95% confidence interval 1.006 to 1.017; P < 0.01). Serum S100A12 levels elevated with the increase in the severity of OSAS (S100A12 levels of 106.04 (range 83.92 to 135.13) ng/ml in mild OSAS group, 133.51 (range 109.64 to 208.95) ng/ml in moderate OSAS group, and 173.04 (range 131.88 to 275.77) ng/ml in severe OSAS group; P < 0.001). Serum S100A12 levels were independently correlated with AHI scores (r = 0.324, P < 0.001) CONCLUSIONS: Serum S100A12 levels were independently associated with the presence and severity of OSAS. These findings suggest that serum S100A12 level could be a potential biomarker for reflecting the presence and severity of OSAS.

Formation of nitrous oxide in a gradient of oxygenation and nitrogen loading rate during denitrification of nitrite and nitrate.

Nitrous oxide (N(2)O) emission has been observed during denitrification of nitrate via nitrite as intermediate. With a laboratory-scale reactor (2.4 L), the N(2)O emission was characterized under a gradient of DO concentration from 0 to 0.7 mg/L, different ratio of nitrite versus nitrate and different nitrite feed mode. The N(2)O emission was influenced by the level of dissolved oxygen (DO) and nitrite accumulation. The higher DO level and the higher ratio of nitrite versus nitrate resulted in the higher N(2)O emission. Using nitrite as sole electron acceptor at the same loading rate, the sequence of N(2)O emission with three different feed modes was: pulse>step-wise>continuous feed. The N(2)O emitted in pulse feed reactors was 3.1-4.2 and 8.2-11.7 folds of that in the step-wise feed and continuous feed reactors, respectively. With continuous feed mode, the impact of DO concentration on the mass of N(2)O emitted was limited while the higher N(2)O emission occurred at the higher nitrite loading rate.

Effect of Yiqi Bufei recipe [see text] on patients with pulmonary incompetence after pneumonectomy.

OBJECTIVE: To study the effect of Yiqi Bufei Recipe ([see text], YBR) on surgical tolerability, pulmonary compensatory function and post-operation rehabilitation in patients with pulmonary incompetence (PI) after pneumonectomy. METHODS: YBR intervention was applied to 60 patients with PI after pneumonectomy (as test group), the pulmonary and cardiac functions changes before and after operation, occurrence of postoperative complications, mortality, and the number of hospitalization days and intensive care unit (ICU) confinement period were observed. Meantime, for the negative and positive controls, the same parameters were observed comparatively in 60 patients with normal lung function, and in 60 patients with PI undergoing a similar operation but untreated with Chinese herbs. RESULTS: Lung function in the test group showed insignificant change before and after operation (P >0.05), while significant decrease was seen in the two control groups (P<0.05). Furthermore, the incidences of post-operation complications and mortality as well as the number of hospitalization days and the ICU confinement period in the test group were significantly lower than those in the positive control group respectively (P <0.05). CONCLUSION: YBR could relieve lung injury after pneumonectomy, improve surgical tolerability, reduce the length of postoperative hospitalization days and ICU confinement period, and lower the incidence of postoperative complications and mortality in patients with PI after pneumonectomy.

Effect of Yiqi Bufei recipe see text on patients with pulmonary incompetence after pneumonectomy / 中国结合医学杂志

<p><b>OBJECTIVE</b>To study the effect of Yiqi Bufei Recipe ([see text], YBR) on surgical tolerability, pulmonary compensatory function and post-operation rehabilitation in patients with pulmonary incompetence (PI) after pneumonectomy.</p><p><b>METHODS</b>YBR intervention was applied to 60 patients with PI after pneumonectomy (as test group), the pulmonary and cardiac functions changes before and after operation, occurrence of postoperative complications, mortality, and the number of hospitalization days and intensive care unit (ICU) confinement period were observed. Meantime, for the negative and positive controls, the same parameters were observed comparatively in 60 patients with normal lung function, and in 60 patients with PI undergoing a similar operation but untreated with Chinese herbs.</p><p><b>RESULTS</b>Lung function in the test group showed insignificant change before and after operation (P >0.05), while significant decrease was seen in the two control groups (P<0.05). Furthermore, the incidences of post-operation complications and mortality as well as the number of hospitalization days and the ICU confinement period in the test group were significantly lower than those in the positive control group respectively (P <0.05).</p><p><b>CONCLUSION</b>YBR could relieve lung injury after pneumonectomy, improve surgical tolerability, reduce the length of postoperative hospitalization days and ICU confinement period, and lower the incidence of postoperative complications and mortality in patients with PI after pneumonectomy.</p>

Rehabilitation of Knee Osteoarthritis in Stroke Patients / 中国康复理论与实践

@#Objective To explore the effective method on the knee osteoarthritis (KOA) of stroke patients.Methods Twenty-four stroke patients with KOA were randomly divided into the treatment group and control group with 12 cases in each group. All patients received facilitation technique exercise, the patients in the treatment group were added with an extra complex therapy of electronic acupuncture, physical and exercise thepapies. All patients of two groups were assessed with visual analogous score (VAS) and Fugl-Meyer Motion Scale (FMMS) before treatment and one course after treatment.Results After treatment, the scores of VAS and FMMS of the patients in the treatment group were significantly better than that in the control group ( P<0.01).Conclusion Multidisciplinary rehabilitation including electronic acupuncture, physical, and exercise is efficiancy to KOA of stroke patients.