The literature aims to explore anti-androgenic particulars against luminal androgen receptor-specific triple-negative breast cancer, thus providing a concise report on the clinical profile of anti-androgens. This review summarizes the types of triple-negative cancer cells, along with the brief involvement of androgen receptors in the luminal type. The paper intricately describes the evidence obtained from the clinical trials and confers the conclusions, in an attempt to help clinicians set forth the optimal strategies in mitigating LAR-TNBC and creating a steadfast foundation for patient care.Triple-negative tumors are progressively delineating their existence over the extended spectrum of breast cancers, marked by intricate molecular heterogeneity, a low overall survival rate, and an unexplored therapeutic approach. Although the basal subtype transcends the group and contributes approximately 80% to triple-negative breast cancer (TNBC) cases, the exceptionally appearing mesenchymal and luminal androgen receptor (LAR) subtypes portray an unfathomable clinical course. LAR with a distinct generic profile frequently metastasizes to regional lymph nodes and bones. This subtype is minimally affected by chemotherapy and shows the lowest pathologic complete response. The androgen receptor is the only sex steroid receptor that plays a cardinal role in the progression of breast cancers and is typically overexpressed in LAR. The partial AR antagonist bicalutamide and the next-generation AR inhibitor enzalutamide are being assessed in standard protocols for the mitigation of TNBC. There arises an inevitable need to probe into the strategies that could neutralize these androgen receptors and alleviate the trajectory of concerning cancer. This paper thus focuses on reviewing literature that provides insights into the anti-androgenic elements against LAR typical TNBC that could pave the way for clinical advancements in this dynamic sphere of oncology. According to a World Health Organization (WHO) report, breast cancer (BC) affects 2.1 million women annually and accounts for the majority of women’s cancer-related fatalities . DiffereThe LAR subclass, representing 15–20% of TNBCs, is characterized by a modest prognosis and shows a minimal response to chemotherapy coupled with a lower complete response following neoadjuvant therapy. To differentially diagnose luminal from nonluminal tumors, a centroid model, namely, clustering among basal and luminal androgen receptors (CABAL), which embraces 426 differentially expressed genes in LAR and non–LAR TNBCs, was used . The LARTriple-negative cancer cells with a diversified nature embody subtypes with varied molecular characteristics. These distinctions at the molecular level render disproportionate responses to chemotherapeutic regimens . The resFirst, the LAR subtype comprises heavily enriched hormonal regulation coupled with the absence of ER expression and displays overlapping patterns with luminal-type breast cancers . The genThe mesenchymal (M) and mesenchymal stem-like (MSL) subtypes are characterized by a cluster of genes linked to cell motility, cellular differentiation, and growth pathways . The M sA class of triple-negative cancer cells exhibits cytokeratins 5/17 and the EGFR/HER1, the genetic attributes of the basally situated epithelial layer of mammary glands, and defines the basal-line subtype . The hisA special feature of the immune-enriched subtype is that it has overlapping features with the other subtypes. The immunomodulatory (IM) correlation represents the genetic expression caused by tumor-infiltrating lymphocytes, with signature tumor cells varying with subtype . This coThe BLIS subtype involves abnormalities in DNA repair, regulation and replication processes. Moreover, BLIS showcases a dysfunctional cell cycle (mitotic prometaphase and cell division events). BLIS constitutes a pathogenesis that implicates few genes to be excessively expressed. These genes embody the protein regulator of cytokinesis 1 (PRC1), the mitotic checkpoint serine/threonine-protein kinase budding uninhibited by benzimidazoles 1 (BUB1) and protein coding genes centromere protein F (CENPF), which contribute to the highly proliferative nature of BLIS . It causBLIA belongs to one of the subtypes of Burstein’s classification of 2015. This subtype portrays the best prognostic parameters when compared to the other three  types of Burstein’s classification. Amplification of the cyclin dependent kinase 1 (CDK)1 gene has been associated with the pathogenesis of BLIA. In contrast to the BLIS subtype, BLIA shows upregulation of B cells, T cells and NK cells. Conversely, the genes involved in the STAT pathway are highly expressed .The androgen receptor is a member of the steroid nuclear receptor family, accompanied by ER and PR. Being expressed in nearly 70–90% of invasive breast carcinomas, it is considered a nuclear hormone receptor with the greatest expression in BC . The preIn the absence of a ligand, AR is bound to heat shock proteins (HSPs) in the cytoplasm, which stabilizes it by exposing the C-terminal ligand binding domain . Upon itSeveral preclinical studies have demonstrated that androgen signaling pathways play a crucial role in the development of malignant breast tissue, with some models implying their role in the progression of breast carcinoma . AR alsoAndrogen receptors can play a dual role in either suppressing tumors or stimulating the oncogenic elements of breast tumors. As a result, it can be established that AR agonists and antagonists can both play a substantial role in mitigating tumors depending on the presence of ERs and subtype of TNBC. If the tumors are both AR- and ER-positive, ARs become capable of competing with ERs to bind with estrogen-related elements. This eventually impairs ER transcription. However, in the case of AR-positive and ER-negative tumors, as seen with typical LAR TNBC, in the absence of ER competition, AR solely binds to androgen-responsive elements, which leads to the strengthening of tumorigenic characteristics and proliferation. This statement deduces the fact that in LAR-positive tumors, AR antagonists work efficiently and provide optimal results in comparison to AR agonists .Additionally, selective androgen receptor modulators (SARMs) are the molecules that can elicit differing degrees of agonistic and antagonistic activity on AR, varying with the tissues. One such SARM, named Enobosarm, has been utilized in LAR-typical TNBC .PIK3CA mutations in AR+ TNBC, which led to the notion of combining PI3K inhibitors or dual PI3K/mTOR inhibitors along with anti-androgenic therapy [Several drug molecules have been developed to inhibit the binding of AR to androgens and the activation of AR because of their role in carcinogenesis. The encouraging results from targeting AR in prostate cancer have provided proof of concept for its application in breast cancers, including TNBC . Androge therapy . Several therapy . Several therapy . Moreove therapy . The mecSeveral novel antiandrogenic agents are currently under investigation in AR-positive TNBC tumors. Clinical evidence suggests a role for anti-androgen therapies that offer an intriguing chemo-free alternative and therefore potentially shift current treatment strategies. Henceforth, we present evidence procured from several clinical trials evaluating anti-androgenic therapy in AR+ TNBC.SEVI (INO-464) has been identified to competitively antagonize androgen receptors and selectively inhibit the intratumoral androgen synthetic actions of cytochrome P45017a (CYP17) lyase . This drIt is a novel nonsteroidal agent that possesses the ability to sensitize AR+ TNBC models. An open-label, phase I/II clinical trial (NCT02580448) evaluated the clinical profile of SEVI in patients with TNBC or ER+/HER2 normal unresectable locally advanced BC. The goal was to determine the safety, efficacy, pharmacodynamic and pharmacokinetic parameters of SEVI. The phase I study included female participants, while phase II enrolled both men and women in their respective cohorts. Of the 175 patients anticipated, 13 patients were suitable to receive SEVI for phase 1. The primary objective of the phase 1 study was to establish the dose recommendations for phase 2 in female participants with BC. The single-dose Cmax was 17.4 ± 4.4 vs. 14.9 ± 4.3 µM, and the area under the curve (AUC) 0–8 h was 99.8 ± 17.9 vs. 78.9 ± 14.1 µM*h at 750 and 600 mg, respectively. These data interpret the dose of 750 mg to be more efficacious. The most common adverse events (AEs) associated with SEVI included fatigue, tremor, and vomiting along with a dose-limiting toxicity (DLT) of confusion, a Grade 3-related AE reported at 750 mg. The drug was found to be well tolerated with similar AE profiles in men and women . SEVI, wEnobosarm, also known as ostarine, MK-2866 or GTx-024, is again a nonsteroidal SARM that serves to inhibit the growth of tumors. An open-label, phase II study (NCT02971761) was designed to assess the safety particulars of enobosarm plus pembrolizumab in addition to the determination of its response rate. Of 18 patients enrolled with a median age of 64 years, 16 patients were chosen for analysis of responses. The results showed a recurrence rate (RR) of 13%, clinical benefit response (CBR) of 25%, progression-free survival (PFS) of 2.6 months, and OS of 25.5 months. This combination, with a few grade 3 AEs comprising dry skin, diarrhea, and musculoskeletal ache, was well tolerated . These rAnother phase II, open-label, multicenter and multinational investigational study enrolling patients (n = 32) was coordinated to determine the safety and efficacy endpoints of enobosarm in patients with AR+ TNBC (NCT02368691). The primary outcome to be evaluated was the CBR, while secondary outcomes included the CBR, best overall response, PFS, time-to-progression, duration of response (DoR), and overall response rate (ORR). This trial was terminated due to a lack of efficacy .Bicalutamide is a nonsteroidal antiandrogen that competitively inhibits the binding of androgens with AR. It downregulates the expression of matrix metalloprotease-2 (MMP-2), matrix metalloprotease-9 (MMP-9) and cyclin D1. It can also induce cell cycle arrest at the G0/G1 phase . An openA phase I/II single-arm, open-label, nonrandomized study (NCT03090165) evaluating the combination of bicalutamide and the CDK4/6 inhibitor ribociclib is under investigation in patients with advanced AR+ TNBC to assess the safety and tolerability profile of the combination .Another ongoing study (NCT02605486) investigated bicalutamide in combination with the CDK4/6 inhibitor palbociclib in AR+ MBC patients to ensure the safety and tolerability of this combination . BicalutEnzalutamide is a second-generation nonsteroidal AR inhibitor that affects multiple steps in the AR signaling pathway, including the inhibition of translocation, cofactor assembly and ultimate transcriptional actions . A phaseAn open-label, randomized, phase Ib/2 trial (NCT02457910) of taselisib (GDC-0032), a PI3K inhibitor, in combination with enzalutamide in patients with AR+ TNBC was conducted to evaluate the side effects and best dose when given in combination and to evaluate the safety and efficacy of this combination. The primary endpoint was CBR at 16 weeks. The results showed a CBR of 35.7% and PFS of 3.4 months. Adverse events included hyperglycemia and skin rash. This trial was terminated due to an interim analysis of toxicity .Abiraterone significantly reduces androgen production by inhibiting cytochrome P450 17 alpha-hydroxylase (CYP-17), an enzyme that plays a substantial role in androgen biosynthetic mechanisms of tumor cells .A phase II trial (NCT01842321) has been conducted evaluating the activity of abiraterone acetate in combination with prednisone in patients with molecular apocrine HER2-negative locally advanced or metastatic BC. Thirty-four patients with AR+ TNBC were included in the study. The primary endpoint, including the CBR at 6 months, was considered, and the secondary endpoints included the ORR, PFS, and safety. Treatment was proven to be well tolerated in some patients. The results comprised a CBR of 20%, an ORR of 6.7%, and a median PFS of 2.8 months. Fatigue, hypertension (HTN), hypokalemia, and nausea were some of the commonly found grade 1 or 2 drug-related AEs .An ongoing trial (NCT04726332) of abiraterone acetate with fulvestrant, prednisone, and XL-102 is currently under investigation. It is a phase 1, open-label, dose-escalation and expansion study that aims to evaluate the safety, tolerability, pharmacokinetics, antitumor activity, and effects of this agent on biomarkers, alone and in multiple combination regimens, in subjects with advanced solid tumors .Orteronel is a novel, orally administered, selective nonsteroidal inhibitor of 17,20-lyase, an essential enzyme in the biosynthetic pathway of androgens. The agent is under clinical evaluation as a potential therapeutic strategy against hormone-sensitive cancers. A phase II study has been established in patients with AR-positive triple-negative tumor cells who have previously been treated with standard therapeutic regimens to evaluate its androgen blocking activity. Twenty-six patients were enrolled with a median age of 57 years. The results showed that the ORR was 4%, the disease control rate (DCR) was 15%, the median PFS was 2 months, and the median OS was 10.2 months. Nausea and fatigue were the most frequently reported AEs. Grade 3/4 AEs comprised HTN, increased amylase, and lipase. Additionally, four patients reported serious adverse events (SAEs) of pneumonitis, chest pain, peripheral edema and prolonged QT under the Grade 2 category with hypokalemia of the Grade 4 category. The treatment regimen was assessed to be well tolerated, notwithstanding the limited clinical activity in the previously treated AR+ TNBC patients. However, the trial closed early due to slow accrual. Of all patients who discontinued treatment, 85% were due to disease progression, and 15% were due to AEs [Fluoxymesterone, also known as CR1447 or 4-hydroxytestosterone (4-OHT), is an androgen receptor modulator that exerts antiproliferative effects in ER + ve and ER-ve/AR+ ve breast cancer cells. It is a small molecule that has two distinct properties. One is the steroidal aromatase inhibitor (AI), and the other property is its capability to bind to the AR with higher affinity. This SARM has the advantage of not causing significant hirsutism, in contrast to the testosterone used for treating AR-positive BC .Finasteride and dutasteride are small molecule inhibitors that block the 5alpha reductase enzyme, resulting in decreased conversion of testosterone to dihydrotestosterone . HoweverTo conclude, the substantiation of targeting AR has opened doors to broadening the treatment strategies for AR+ TNBC with encouraging results from clinical trials. As the only side effects encountered are nausea and fatigue, anti-androgenic monotherapy has been beneficial if the prevention of toxicity is prioritized (exception being ortorenol).The combinations of AR antagonists with the immunotherapeutic agents pembrolizumab and prednisone have shown enhanced efficacy but with a rise in grade 2 and 3 events. Bicalutamide and seviteronel have exhibited remarkable safety profiles along with improvement in the survival of patients. Further studies are being conducted to investigate the combination of AR-targeting therapies with targeted chemotherapeutic therapies such as CDK inhibitors and PI3K inhibitors along with ICIs. Several completed and ongoing clinical trials assessing anti-androgens in AR+ TNBC are summarized in AR-positive TNBC presents a dismal prognosis with a higher mortality rate and a challenging clinical course. The conventional chemotherapeutic regimens had a paucity of requisite clinical responses, and this demanded the discovery of a novel standpoint in combating the formidable battle against LAR typical TNBC. With this emerged the idea of targeting the ARs, which showcased substantial expression in luminal triple-negative cells. Androgen receptors have been established to receive stimulations from androgens and support the mediation of hormonal regulation in carcinogenetic events. Despite the demonstration of encouraging efficacy endpoints by a plethora of clinical trials assessing anti-androgenic agents, the data still exhibit controversies. Although approaches utilizing bicalutamide and seviteronel have shown promising results, few studies evaluating this class of drugs have evidenced the shortcomings of unsatisfactory efficacy, notable disease progression, and adverse event profiles. Anti-androgenic drugs in combination with CDK inhibitors, PI3K inhibitors and ICIs are being assessed and anticipate a propitious response. Improvements are being witnessed in formulating these drugs, and newer anti-androgens with exceptional properties can be expected in the near future. This lends us to the conclusion that the anti-androgenic approach is capable of paving an optimistic path against LAR-TNBC.


Compound 7 demonstrated promising binding affinities with the target enzymes Mpro, PLpro, RdRp, and RBD with docking scores of −11.4, −9.4, −8.2, and −6.8 kcal/mol, respectively. In addition, compound 7 exhibited MM-GBSA//100 ns MD docking score of −35.9 kcal/mol against Mpro. Structural and energetic analyses revealed the stability of the 7-Mpro complex over 100 ns MD simulations. In addition, compound 7 obeyed Lipinski’s rule of five, as it has acceptable absorption, distribution, and oral bioavailability inside the body. Therefore, compound 7 is considered as a promising starting point for designing potential therapeutic agents against Covid-19.In the present study, a new category of 1,3,4-thiadiazoles was developed by submitting methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate to react with the appropriate hydrazonoyl halides in presence of few drops of diisopropyl ethyl amine. The chemical structures of the newly synthesized derivatives were inferred by means of their micro-analytical and spectral data. Utilizing combined molecular docking and molecular dynamics techniques, the binding affinities and features of the synthesized compounds were evaluated against four SARS-CoV-2 target enzymes, namely, main protease (MThe online version contains supplementary material available at 10.1007/s11224-022-01985-1. A new strain for SARS-CoV-1 identified recently as SARS-CoV-2 in late December 2019 resulted in serious physical and psychological damages to the human health; a massive outbreak initially in Wuhan, China, and spread rapidly in different nations around the global in a short time . It is aOn the other hand, 1,3,4-thiadiazole moieties have been reported for their pharmaceutical properties. Many antiviral drugs like acetazolamide, besaglybuzole (glybuzole), and furidiazine (triafur) were reported to append the 1,3,4-thiadiazole in their constructors–13.Urgent needs for develoment novel anti-Covid19 agents have directed us to synthesize some new bioactive heterocyclic molecules. In the present study, we aimed to identify potential Covid-19 inhibitors through a computer-based molecular docking and molecular dynamics techniques –16. In a2) acts as key molecule for the design of new desired 1,3,4-thiadiazole compounds. It is allowed to react with a selected group of hydrazonoyl halide derivatives by grinding method “grindstone chemistry” under solvent-free conditions with the addition of catalytic amount of DIPEA (diisopropyl ethyl amine) to afford the target molecules 3–7, (Scheme Methyl 2-(4-hydroxy-3-methoxybenzylidene)hydrazine-1-carbodi-thioate  [M+], which agrees with its molecular formula C23H19N5O3S, as represented in Fig. The chemical composition of the target molecule pro, PLpro, RdRp, and RBD of S-protein. The predicted docking scores are tabulated in Table 7 inside the active site of Mpro, PLpro, RdRp, and RBD are displayed in Fig. The molecular docking technique , 18 was 7 exhibited binding affinities against all the selected targets better than the reference drug (Darunavir)  Fig. .pro with binding energies ranged from −11.4 to −6.4 kcal/mol. The high docking scores of the studied compounds with Mpro would be returned to their ability to form hydrogen bonds, hydrophobic and van der Waals interactions with the amino acid residues of active sites  through pi-stacked interactions at distances 4.27, 5.51, and 5.58 Å, respectively. Further, compound 7 interacted with the residues Arg116 and Phe35 of the target RdRp through pi-stacked interactions at distances 5.89, and 3.92 Å, respectively. Finally, it docked with RBD through two hydrogen bonds and one pi–pi interaction with the amino acid residues Tyr385, Arg393, and Phe40.Compared to MGbinding) were then calculated using the molecular mechanics-generalized born surface area (MM-GBSA) approach based on the collected snapshots for Mpro, PLpro, RdRp, and RBD of spike protein over the production stage of 25 ns. The calculated MM-GBSA binding energies are listed in Table Towards more reliable binding affinities, the molecular dynamics simulations were performed for all synthesized compounds in complex with SARS-CoV-2 targets. The binding energies , root-mean-square deviation (RMSD), and root-mean-square fluctuation (RMSF) were performed over 100 ns MD simulations.The interaction nature and stability of compound 7 and Darunavir in complex with SARS-CoV-2 Mpro was estimated using the correlation between the binding energy per-frame and time. MM-GBSA binding energy was subsequently evaluated per-frame for the most promising compound with each target and displayed in Fig. 7-Mpro, and darunavir-Mpro complexes, respectively.The stability of compound 7, and Darunavir and the residue Glu166 through the 100 ns MD simulations would reflect a strong indication of the high stability of the identified compounds inside the Mpro active site. The CoM distances were inspected over the 100 ns MD simulations and represented in Fig. 7 bound more tightly to the Mpro complex compared to Darunavir.Interestingly, investigating the center-of-mass (CoM) distance between the compound 7-Mpro and darunavir-Mpro complexes were evaluated using the root-mean-square deviation (RMSD). The conformational change of backbone atoms of the most promising three compounds in complex with SARS-CoV-2 Mpro has been compared with initial conformations over 100 ns MD simulations as shown in Fig. 7- Mpro and darunavir-Mpro complexes, the distance was noticed to be below 0.25 nm and the overall stability of these compounds inside the SARS-CoV-2 Mpro active site. These results confirmed that compound 7 is tightly bonded in the active site and does not affect the overall topology of SARS-CoV-2 Mpro.The structural changes of ADMET studies of the prepared molecules exhibited that they have acceptable absorption and distribution properties in the range of (91–80-98.76%) and 0.53–0.70), respectively. The physiochemical properties of the compounds exhibited acceptable values, as they have molecular weights and partition coefficients in the range of (256.35–445.49 g/mol), and < 5, respectively. Moreover, the molecules have no toxicity and carcinogenicity. All tested compounds showed good oral bioavailability within the body as they obeyed Lipinski's rule of five , papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and receptor-binding domain (RBD) of the spike protein. The molecular docking studies and molecular dynamics simulations exhibited the promising binding affinity of compound 7 with all targets. Therefore, it could be select as promising chemical moiety for designing of future inhibitors as anti-Covid-19 agents.In this study, a new series of 1,3,4-thiadiazole derivatives was synthesized, characterized, and theoretically evaluated as Covid-19 inhibitors against four SARS-CoV-2 targets namely, main protease (M1H- and 13C-NMR spectra were recorded in (CD3)2SO solutions on a BRUKER 500 FT-NMR system spectrometer, and chemical shifts are expressed in ppm units using TMS as an internal reference. Mass spectra were recorded on a GC–MS QP1000 EX Shimadzu. Elemental analyses were carried out at the Microanalytical Center of Cairo University.All melting points were uncorrected and measured using electrothermal device. The IR spectra were recorded (KBr discs) using Shimadzu FT-IR 8201 PC spectrophotometer. 2  and the selected derivative of the hydrazonoyl halides (5 mmol) and 2–3 drops of DIPEA as a catalyst, were ground well in an open mortar with a pestle for 5–7 min. at RT till the mixture turned into melt. The grinding was continued for approximately 5–10 min, and the reaction was monitored by TLC. The solid was collected and washed with (water/ethanol) the recrystallized from the proper solvent to give the desired derivatives 3–7, respectively.A mixture of compound −1): v 1554 (C = C), 1599 (C = N), 1712 (C = O), 3471 (OH); 1H-NMR (DMSO-d6): δ 9.65 , 8.29 , 7.90 , 7.33–7.45 , 7.17 , 6.83 , 4.15  3.82 ,1.29 ;13C-NMR : δ 13.97 (CH3), 55.54 (OCH3), 62.75 (CH2), 110.18 (Ar.), 115.61(Ar.), 122.40 (Ar.), 122.56 (Ar.), 125.51 (Ar.), 127.32 (Ar.), 127.92 (Ar.), 129.07 (Ar.), 138.61 (Ar.), 142.22 (Ar.), 147.92 (Ar.), 149.51(CH), 156.12 (Ar.), 158.07 (Ar.), 163.75 (C = O); MS m/z (%): 398 . Anal. Calcd. for “C19H18N4O4S” (398): C, 57.28; H, 4.55; N, 14.06. Found: C, 57.34; H, 4.51; N, 14.01%.Yellow crystals (95%); m.p. 172–174 °C, FT-IR , 1600 (C = N), 1705 (C = O), 3502 (OH); 1H-NMR: δ 9.65 , 8.29 , 7.76 , 7.31–7.33 , 7.18 , 6.84 , 4.33 , 3.81 , 2.36 ,1.30 ;13C-NMR: δ 13.97 (CH3), 20.64 (CH3), 55.53 (OCH3), 62.72 (CH2), 110.19 (Ar.), 115.58 (Ar.), 122.35 (Ar.), 122.56 (Ar.), 125.51 (Ar.), 129.46 (Ar.), 136.09 (Ar.), 136.91(Ar.), 141.88 (Ar.), 147.91 (Ar.), 149.55 (CH), 155.94 (Ar.), 158.08 (Ar.), 163.81 (C = O); MS m/z (%):412 . Anal. Calcd. for “C20H20N4O4S” (412): C, 58.24; H, 4.89; N, 13.58. Found: C, 58.19; H, 4.83; N, 13.53%.Yellow crystals (92%); m.p. 180–182 oC, FT-IR: v 1550 (C = C), 1600 (C = N), 1678 (C = O), 3417 (OH); 1H-NMR: δ 9.65 , 8.31 , 7.34–7.97 , 7.16 , 6.81, 3.80 , 2.48 ; 13C-NMR: δ 25.14 (CH3), 55.54 (OCH3), 110.01 (Ar.), 115.59 (Ar.), 122.60 (Ar.), 125.49 (Ar.), 127.43 (Ar.), 129.13 (Ar.), 138.54 (Ar.), 147.87 (Ar.), 149.55 (CH), 150.17 (Ar.), 156.33 (Ar.), 164.04 (C = O); MS m/z (%): 368 . Anal. Calcd. for “C18H16N4O3S” (368): C, 58.68; H, 4.38; N, 15.21. Found: C, 58.63; H, 4.32; N, 15.16%.Orange crystals (82%); mp. 212–214 oC, FT-IR: v 1541 (C = C), 1600 (C = N), 1681 (C = O), 3502 (OH); 1H-NMR: δ 9.64 , 8.27 , 7.80 , 7.30–7.32 , 7.13 , 2.34 , 6.80 , 3.79 , 2.51 ;13C-NMR: δ 20.66 (CH3), 24.95 (CH3), 55.52 (OCH3), 109.97(Ar.), 115.58 (Ar.), 122.53 (Ar.), 125.54 (Ar.), 129.48 (Ar.), 136.22(Ar.), 136.97 (Ar.), 147.94(Ar.), 149.53 (CH), 149.95 (Ar.), 156.07 (Ar.), 164.13 (C = O); MS m/z (%): 382 %. Anal. Calcd. for “C19H18N4O3S” (382): C, 59.67; H, 4.74; N, 14.65. Found: C, 59.73; H, 4.70; N, 14.62%.Orange solid (81%); mp.191–193 °C, FT-IR: v 1539 (C = C), 1600 (C = N), 1681 (C = O), 3337 ;1H-NMR: δ 10.68 , 9.65 , 8.36 , 8.15 , 7.75 , 6.86–7.85 , 3.83 ;13C-NMR: δ 55.5 (OCH3), 110.05 (Ar.), 115.61(Ar.), 120.96 (Ar.), 122.34 (Ar.), 122.43 (Ar.), 124.70 (Ar.), 125.58 (Ar.), 126.94 (Ar.), 128.82 (Ar.), 128.93 (Ar.), 137.54 (Ar.), 138.94 (Ar.), 147.33 (Ar.), 147.95 (Ar.), 149.54 (CH), 155.89 (Ar.), 156.26 (Ar.), 164.16 (C = O); MS m/z [%]: 445 (M+), 444 (75), 317 (30), 281 (28), 255(80), 151(52), 127(48); Anal. Calcd. for “C23H19N5O3S” (445): C, 62.02; H, 4.30; N, 15.72%. Found: C, 62.06; H, 4.27; N, 15.65%.Yellow solid, m.p. 251–253 °C; yield (95%); FT-IR: pro; PDB code: 6LU7) [pro; PDB code: 6W9C) [pro, PLpro, RdRp, and RBD of S-protein, and all missing hydrogen atoms were added [The crystal structures of SARS-CoV-2 main protease (Me: 6LU7) , papain-e: 6W9C) , RNA-depe: 6W9C) , and rece: 6W9C)  were sele: 6W9C) . Besidesre added .The chemical structures of the synthesized compounds were manually constructed, and their 3D structures were generated using Open Babel 2.4.1 tool –27. All pro, PLpro, RdRp, and RBD of S-protein targets were prepared according to PyRx protocol. The docking algorithms were conserved to their default values, except the number of genetic algorithms (GA) run and the maximum number of energy evaluation . In the current study, GA and eval were set to 250 and 25,000,000, respectively. The docking grid was set to 25 Å × 25 Å × 25 Å with a spacing value of 0.375 Å [pro, PLpro, RdRp, and RBD of S-protein. The partial atomic charges of the examined compounds were estimated using the Gasteiger method [Molecular docking calculations , 29–33 w 0.375 Å , 35. Ther method . The preMolecular dynamics simulations were performed for the examined compounds in complex with the four studied SARS-CoV-2 targets using AMBER16 software. In MD simulations, the General AMBER force field (GAFF2)  and AMBEG) is estimated as:Evdw and Eele are the van der Waals and electrostatic energies, respectively. GGB is the electrostatic solvation free energy calculated from the generalized Born equation, and GSA is the nonpolar contribution to the solvation free energy from the solvent-accessible surface area (SASA). Solute entropy contributions to binding energies were neglected, and a single-trajectory approach was employed, in which the coordinates of each molecule, receptor, and complex were isolated from a single trajectory.The binding free energies of the examined compounds with SARS-CoV-2 targets were estimated using molecular mechanical-generalized Born surface area (MM-GBSA) approach , 41. ForThe freely accessible online softwares such as admetSAR, SwissADME, and Mol inspiration are used to predict ADMET and drug-likeness properties of compounds.Supplementary file1 (DOCX 2.23 MB)Below is the link to the electronic supplementary material.


BackgroundThe concept of focused rehabilitative care and a dedicated rehabilitation setup is fairly less known among the people of developing countries. The main objective of the study is to assess the effect of late-onset stroke rehabilitation on its overall prognosis and to see whether and how the late initiation of rehabilitation would pose a significant effect on functional recovery and adverse medical outcomesMethodsA single-center, prospective observational study was conducted in a tertiary rehabilitation center for a duration of one and a half years. The subjects admitted to the Department of Physical Medicine and Rehabilitation were divided into three groups with respect to the onset to admission interval (OAI). Patients who got admitted within 30 days (OAI≤ 30 days) were considered the early rehabilitation group. OAI between 31 and 150 days was the late rehabilitation group and OAI of 151 days or more was the very late rehabilitation group. Barthel Index (BI), Modified Rankin Score (MRS), and 6-minute walk test (6MWT) were used as functional outcome measures at admission and discharge from indoors.ResultsMaximum complications were observed in the late rehabilitation group, i.e. 2.75±2.74, with an overall mean of 2.02±2.04 (p=0.003). Functional recovery assessed using BI shows a significant difference between the early (35.79±8.86) and late (40.62±10.5) rehabilitation groups (p= 0.0005). 6MWT at discharge showed significant improvement in the early rehabilitation group (p=0.005).ConclusionEarly onset of rehabilitation showed better functional recovery and fewer adverse medical outcomes in stroke patients. A longer length of hospital stay (LOHS), with a mean duration of 88 ±2 days was needed for patients with higher OAIs. Stroke is an acute event of cerebrovascular origin causing focal or global neurological dysfunctions lasting more than 24 hours. It is the leading cause of ensuing complications and long-term disability . The GloThe American Stroke Association has recommended that rehabilitation can be started within two days after the onset of stroke in medically stable patients . Even thUnfortunately, prevailing studies on stroke rehabilitation outcomes are not consistent, and the effectiveness of stroke rehabilitation programs is still debatable . Many stIn contrast to developed countries, the concept of focused rehabilitative care and a dedicated rehabilitation setup is fairly less known among the Indian population. More often, after discharge from an acute care facility, unfocused therapy for a short duration of time is all that the patients get. Access to early rehabilitation following a stroke is not easily available in developing countries and a lack of awareness about the impact of early rehabilitation adds to comorbidities. However, multicenter studies with large sample sizes are required, which will help in policy-making for the rehabilitation of stroke patients. Hence, this pioneer Indian research was conducted with the main objective of studying the effect of late-onset stroke rehabilitation on its overall prognosis and seeing whether and how the late initiation of rehabilitation would pose a significant effect on the outcomes and medical complications.This pioneering study was a prospective, observational study in a single-center, rural-based national institute of India within a period of one and a half years. A study sample size of 30 stroke patients (n=30) was calculated using the Cochrane method. Out of 41 patients admitted to the department of Physical Medicine and Rehabilitation, consecutive 30 patients meeting the inclusion criteria were recruited for the study. Scientific and ethical committee approval was taken as per national legislation and the declaration of Helsinki. The study has been approved by the institution-recognized ethical committee of JPM Rotary Eye Hospital and Research Institute vide IRB No. IECJREH/A14/2020 dated 27/02/2020. Consent was taken from all the patients before recruitment for the study. Demographic and clinical data were collected in the data collection forms. The tables were then deduced from the collected data for further consideration.The research included cases with age > 18 yrs, first-ever stroke, either ischemic or hemorrhagic origin, hemodynamically stable, no or minimal cognitive impairment, and not having received rehabilitation services before. Subjects with ages less than 18 years, previous cerebrovascular accidents, a bilateral (B/L) cerebral lesion, cognitively impaired, incomplete/complete rehabilitation services received previously were excluded from the study. Patients with medical co-morbidities, namely, type 2 diabetes mellitus (T2DM), hypertension (HTN), hypercholesterolemia, complications of stroke such as spasticity, urinary tract infections (UTIs), pressure ulcers, falls, seizures, and shoulder pain were considered in the study. Standardized stroke rehabilitation protocols were followed in therapy departments for all patients as per institutional guidelines. However, the customization of the procedure for different groups was not supervised by the principal investigator. The optimization of hand function for the basic activities of daily living (ADL) of stroke patients was assessed and managed by the occupational therapy department. The primary criteria for discharge from the hospital were after the patient achieved the set rehabilitation goal based on the type and severity of the stroke. The outcome measures were recorded at admission and during discharge from the hospital.Outcome measuresRehabilitation outcomes were gauged using scales: admission and discharge Barthel Index (BI) and Modified Rankin Score (MRS) for ADL) -13; 6-miRehabilitation units were used to consider the intensity of stroke rehabilitation received by a patient . One rehAccording to a Japanese study by Yagi and associates, an average intensity per day of 3.0 or more was considered intensive rehabilitation . The majFor the ease, and systematicity of the study, the subjects were divided into three groups with respect to the onset to admission interval (OAI) (time since occurrence/onset of stroke till admission to the rehabilitation unit). Patients who got admitted within or equal to 30 days (OAI≤ 30 days) were considered the early rehabilitation group. OAI between 31 and 150 days was the late rehabilitation group. OAI of 151 days and more were placed into the very late rehabilitation group.Data analysisThe data were entered in Microsoft Excel . Descriptive statistics were used to measure numbers and frequencies. A multivariable logistic regression analysis using the regression function in Microsoft Excel was used. Inter-group analyses were done using analysis of variance (ANOVA). A p-value of < 0.05 was considered statistically significant.The mean age of the study population was 58.03±13.14 years. The very late group showed the highest mean age of 68.3±9.07 years. There is a significant difference in the mean age of the three groups. The LOHS was lowest for the early rehabilitation group, which was 46.79±8.91. The very late group needed the highest LOHS of around 88±2 days.Our study population had a majority of male patients. Out of the 30 patients in the study, 25 of them were male subjects and 23 of the 30 had hypertension, which was the most common co-morbidity associated with the study. Diabetes mellitus was the second most common co-morbidity associated with 18 patients. There was no significant difference in the type of stroke. There were 16 hemorrhagic stroke patients compared to 14 ischemic stroke patients. The right-sided hemiparetic presentation was more common than the left-sided presentation (n=18 vs n=12)  overall followed by hemiplegic shoulder pain (n=13). Hemiplegic shoulder pain was also the most common complication incriminated in the early rehabilitation group (n=9) and spasticity in the late rehabilitation group (n=8). Five of the 19 subjects in the early group had at least one episode of seizure. UTI as well as falls were more prevalent in both the early and late groups. In the very late group, all three subjects had spasticity and one out of the three had a Grade III pressure injury . Also, the change in BI for the early rehabilitation group was 35.79±8.86, and that for the late group was 40.62±10.5 (p= 0.0005)  . The depression score of the HADS was maximum in the very late group at admission (16.3±1.5)  and 16 of these subjects were admitted after one year ,22. An OThe study we conducted showed an overall length of hospital stay (LOHS) of 56.13±15.73 days. The mean LOHS in the early rehabilitation group was 46.79±8.91 days, that for the late group was 66.37±5.21, and the very late group required a mean LOHS of 88±2 days to achieve basic ADL gains. Optimization of ADL was assessed by the occupational therapy department of the institute. The study done by Savas and his associates was the only study that considered LOHS as a variable. They divided their study population into only two groups. The mean LOHS in the <30 days OAI group was found to be 34 days and in the >30 days group, it was 30.08 days . An ItalIn our study, 76.66% of the study population had hypertension, which was the major co-morbidity associated. Diabetes mellitus was the second most common co-morbidity associated with the study group followed by hyperlipidemia. Savas et al. also showed a similar percentage of co-morbidities with hypertension being the most common followed by diabetes . Salter Hemorrhagic stroke was the most common type of stroke (53.33%) followed by ischemic stroke (46.66%) in our study, even though the majority of the cases in the early rehabilitation group were ischemic 57.89%). M. Siddique and co-workers, Salter et al., Susan Raju et al., and Y. Ng et al., also concluded that the ischemic strokes were more than the hemorrhagic strokes in their study group 9%. M. Si,26,27. SRight-sided impairment was most commonly seen in most of the studies ,20,23. TConsidering all the patients in our study, the mean number of medical complications was 2.02±2.04. Our study showed that 23.33% of the study population had UTIs, 30% of them had fallen, and 43.33% had shoulder pain as a complication. While in a study by Janus Laszuk and co-workers, UTI was the most common complication (23.2%), followed by falls (17.9%) and shoulder pain (14.9%) . DepressA mean change in Barthel Index score of 29 from admission to discharge was shown in their study by Yagi and his co-workers . A mean The majority of the subjects in the late and very late rehabilitation groups were found to be depressed at admission according to the HADS depression score  while the majority of the early rehabilitation population had anxiety at admission (mean HADS-A score of 12.52±2.75) with high statistical significance. The mean HADS-A score at admission in our study was 12.03±2.77 and the mean score of HADS-D at admission was 9.76±3.77 and that on discharge was 8.73 and 8.43, respectively. In comparison, in a study from Thailand, the mean admission HADS-A score was 7.50, the mean admission HADS-D score was 8.46, and that at discharge was much less in the normal score range . This suThe six-minute walk test (6MWT) was considered in our study as an outcome measure for ambulation. It was found that the early rehabilitation group was able to walk the longest at discharge than the late and very late groups, thus suggesting that early initiation of rehabilitation would show better functional outcomes.Spasticity was assessed by the Modified Ashworth Scale (MAS). Our study showed that the early rehabilitation group had no spasticity at discharge while the very late group had remnant spasticity at discharge. Pressure ulcers were seen in two patients of the study group who were neglected due to socio-economic and family constraints.LimitationsAs a single-center observational study with a limited study duration, the sample size is small. A larger sample size is desirable to generalize the study result on the stroke population of developing countries. The study was set up in a rural background and hence urban statistics are unaccounted for. Although standard rehabilitation protocols were followed for all patients as per institutional guidelines for stroke rehabilitation, customization of the procedure for different groups was not supervised by the principal investigator.RecommendationA large sample size controlled study with a standardized and monitored rehab treatment protocol considering both urban and rural populations throughout India is the need of the hour.Further, ground-breaking research is needed that brings about consensus regarding the exact time to start rehabilitation and the exact intervals to categorize early or late rehabilitation.A study that would discuss the measures, and interventions taken to achieve the functional outcomes in stroke patients and their comparison at admission and discharge would add further depth to the current study.The earlier the initiation of rehabilitation, the better the functional outcomes and the lesser the medical comorbidities. The result of our study supports that the early onset of rehabilitation is related to a good recovery of ambulation and functional independent status. A longer LOHS was needed for later OAIs. Indian rural and sub-urban populations are still devoid of that early, first emergency care, as well as the equally pivotal physiatrist consult. Every case should be considered different; re-diagnosis and localization of the lesions should always precede an achievable goal setting, which will lead to better functional outcomes.


Active rehabilitation involving subsymptom threshold exercise combined with education and support promotes recovery in youth with concussion but is typically delivered in person, which may limit accessibility for families because of a lack of services in their communities or logistical challenges to attending in-person sessions.This paper describes the evidence-based and theory-informed development of the Tele-Active Rehabilitation (Tele-AR) intervention for pediatric concussion, which was specifically designed for remote service delivery.The intervention was designed by clinician-researchers with experience in pediatric concussion rehabilitation following the Medical Research Council guidance for developing complex interventions. Development involved a critical review of the literature to identify existing evidence, the expansion of the theoretical basis for active rehabilitation, and the modeling of the intervention process and outcomes.Concussion & You self-management program, which covers topics related to energy management, nutrition, hydration, sleep hygiene, and return to activity. Elements of self-determination theory are incorporated to support motivation and engagement. We present a logic model describing predicted intervention effects using a biopsychosocial conceptualization of outcomes after concussion.Tele-AR is a 6-week home exercise and education and support program facilitated through weekly videoconferencing appointments with a clinician. Exercise consists of low- to moderate-intensity subsymptom threshold aerobic activity and coordination drills that are individualized to participant needs and interests (prescribed for 3 days per week). Education includes the evidence-supported The Tele-AR intervention may help to increase access to care that improves recovery and promotes a timely return to activity in youth with concussion. Future research is needed to evaluate the feasibility and efficacy of this approach. Concussion is a common injury among children and adolescents that may result in physical, cognitive, emotional, or sleep-related symptoms -3. AlthoOccupational performance, which refers to the ability to choose, organize, and satisfactorily perform meaningful occupations , is ofteCurrently, recovery from concussion among children and adolescents is being reconceptualized to emphasize resumption of everyday activities and general well-being, rather than solely the resolution of postconcussion symptoms . EvaluatGrowing evidence supports an active approach to concussion rehabilitation involving guided physical activity. Several studies demonstrate the efficacy of subsymptom threshold aerobic exercise for reducing postconcussion symptoms -24. SomeThe rationale for an active approach to concussion rehabilitation has been rooted in the benefits of physical exercise to promote biological recovery  and psychological well-being  ,33-35. TThe theoretical model of active rehabilitation described by Gagnon et al  endorsesTo date, active rehabilitation has typically been conducted through in-person sessions at a specialty clinic or research facility ,28,30,31This paper describes the evidence-based development of, and theoretical rationale for, the Tele-Active Rehabilitation (Tele-AR) intervention for youth with concussion, which was specifically designed to promote return to activity in a remote service delivery format. A detailed overview of the intervention is also provided.This study was approved by the University of Toronto Health Sciences Research Ethics Board (REB reference number 00039179). Participants provided informed written consent to participate in the study.The Tele-AR intervention was designed by a team of clinician-researchers  with experience in pediatric concussion rehabilitation, based on clinical experience and a critical review of published literature. The Medical Research Council (MRC) framework for developing and evaluating complex interventions ,51 guideAccording to the MRC framework, intervention development is an iterative process involving integration of current evidence and appropriate theory, followed by a phased testing approach involving a series of pilot studies before a definitive evaluation . The devWe drew on guidance from Campbell et al  and FaesIdentifying existing evidenceDefine and quantify target populationReview of concussion epidemiology among youthProject team consultation to determine target populationDefine health outcome and outcome measuresReview of current consensus definition of recovery from concussionIdentification of appropriate measurement toolsUnderstand factors that cause and sustain the problemReview of factors that influence concussion recovery in youthIdentification of existing biopsychosocial models of concussionIdentify similar interventionsCritical review of literature pertaining to active rehabilitation interventions for youth with concussionReview of best practice recommendations for telerehabilitation and telehealth self-management interventionsDefine target contextReview of guidelines for telemedicine in concussion managementIdentifying appropriate theoryReview of existing theoretical rationales for active rehabilitationReview of health behavior change theoriesIntegration of health behavior change theory in the interventionModeling process and outcomesProject team consultation to design intervention componentsDevelopment of logic model to describe anticipated effects of intervention componentsMethods section.Results from the development stage are described in the following sections, organized according to the MRC headings and key tasks identified in the The Tele-AR intervention targets adolescents (aged 13-17 years) who continue to experience symptoms at least 2 weeks after concussion. All mechanisms of injury are considered, including sport, falls, and motor vehicle accidents.In recent decades, health care usage for pediatric concussion has increased substantially in Canada  and the Primary health outcomes for the Tele-AR intervention include postconcussion symptoms and perceived occupational performance, a measure of performance in daily activities.The most recent 2016) international consensus statement on sports-related concussion defines recovery as the resolution of concussion symptoms and return to normal activities, including school, work, and sport 016 inter and are Current evidence indicates that persistent symptoms and activity limitations after concussion are best understood through a biopsychosocial perspective ,39,60. ABiological or physiological factors after concussion include autonomic nervous system and cerebral autoregulatory dysfunction , impaireThere is growing recognition that psychological mechanisms related to cognitive, behavioral, and emotional reactions to concussion influence outcomes . NegativThe social influences of concussion are poorly understood. Adolescents with concussion report limitations in school function and social activities -9. QualiAccess to appropriate clinical care may influence how these biological, psychological, and social factors are experienced by the individual and, in turn, their effects on recovery. A systematic review found several studies showing that earlier initiation of clinical care after concussion leads to quicker recovery . Timely There are currently significant challenges to accessing timely appropriate care for concussion in Canada . Studiesactive rehabilitation, exercise, physical activity, concussion, mild traumatic brain injury, youth, and adolescents. Additional pertinent literature was identified through forward and backward searching of reference lists as well as literature previously known to the authors. Intervention characteristics among the studies included in the review are detailed in A critical review of the literature describing active rehabilitation approaches to concussion was performed in the fall of 2019. Key articles were located through search in Google Scholar and PubMed using keywords that included Findings from the review indicated that active rehabilitation interventions typically last 6 weeks and involve a variety of components, including aerobic exercise ,32,80-84Although key components are not fully understood, a study of multimodal active rehabilitation found that youth identified the education, aerobic exercise, and sport coordination drills as most helpful . A combiPublished active rehabilitation interventions typically involve a home exercise program performed several (3-7) days per week and weekly appointments with a clinician. Appointments have occasionally been conducted by telephone ,31,32, wSystematic reviews of telerehabilitation -47 and rThe aforementioned literature provided the foundations for the design of the Tele-AR intervention. On the basis of this literature, it was determined that the intervention should be a 6-week program comprising aerobic exercise, coordination drills, and comprehensive individually tailored education and support to train self-management skills. Telehealth literature indicated that weekly appointments should involve a review of symptoms and activity performance with provider feedback, continued education regarding symptom management strategies, and support to promote motivation and adherence to the home program ,86.Tele-AR could be an accessible intervention to reduce the burden of pediatric concussion, especially among those identified as high risk for prolonged recovery . It compRecommendations for the use of telemedicine in concussion management specify the need for initial in-person medical assessment to confirm the diagnosis of concussion as well as regular medical follow-up ,87. TeleWe drew on self-determination theory (SDT) to expand the theoretical foundation for active rehabilitation to address motivation, a key determinant of engagement and outcomes in rehabilitation ,89. MotiSDT has been identified as a useful framework for conceptualizing motivation in pediatric rehabilitation . SDT is The Tele-AR intervention is designed to support the 3 psychological needs outlined in SDT to promote motivation and engagement in the program and regular daily activities. Each element is briefly described in the following sections. The Tele-AR intervention aims to promote a sense of competence by helping adolescents set optimal challenges and increase self-efficacy. This involves gradually increasing experiences of success through participation in school, exercise, and other meaningful activities. An action plan is developed with each participant to identify how they will implement strategies to support recovery . Second, participants are taught to self-monitor exertion during activities to prevent significant symptom exacerbation. They are encouraged to monitor the time during which they engage in activities such as schoolwork and screen use to facilitate gradual progression. Third, the clinician provides feedback and encouragement during appointments using a strengths-based approach, whereby participants are prompted to discuss what has gone well and which strategies they used to support success. An opportunity is provided for participants to identify barriers they are encountering and explore potential solutions with the clinician. Finally, strategies are discussed for dealing with stressful situations that could undermine competence, such as relaxation techniques  and seeking help.Autonomy is supported by providing meaningful rationales for active rehabilitation, integrating participant perspectives in program development, and providing choice. The rationale for the active rehabilitation approach is explained to participants at the beginning of the intervention. Education is provided using nonjudgmental language integrating participant perspectives and emphasizing freedom of choice . Participants are engaged in coconstructing the home program based on their needs and interests, including choice about specific exercises. The Tele-AR intervention is designed to empower youth to take responsibility for their recovery through self-management and coping skills. In a previous study, parents reported that active rehabilitation helped their children become more accountable for their recovery by teaching them to self-monitor their condition . Remote invisible injury, such as comparing energy levels to a cellphone battery [Relatedness  is fostered by the clinician through active listening, expressing empathy, and encouraging perspectives and questions from the participant. Studies from a variety of rehabilitation disciplines, including physiotherapy , occupat battery . ParticiModeling aims to define intervention components, explain how they relate to each other, and describe the mechanism through which they influence desired intervention outcomes . Figure Several reviews demonstrate the efficacy of aerobic exercise for reducing postconcussion symptoms ,23. ProgAccording to Gagnon et al , the purEducation and support are essential components of concussion management consistently recommended among evidence-based guidelines . EducatiIdentifying and Applying Theory section, the Tele-AR intervention is designed to foster satisfaction regarding competence, autonomy, and relatedness to strengthen motivation and self-determination. Fulfillment of these needs is believed to support participation in the program. It is also hypothesized that increased self-determination through active rehabilitation will directly contribute to symptom reduction and improved occupational performance.As described in the The Tele-AR intervention is a 6-week home program facilitated through weekly videoconferencing appointments with a rehabilitation clinician . It consists of (1) aerobic exercise, (2) sport coordination drills, and (3) comprehensive concussion education and support. The following sections provide a detailed description of the intervention.Assessment section). The second appointment consists of a participative concussion education session and collaborative coconstruction of the home program, integrating the participant’s individual needs and interests within the three components .During weeks 1 to 6, participants are asked to perform the home exercise program 3 days per week and meet with the research clinician once per week. The purpose of weekly appointments is to provide continued education and support, modify the exercise program as appropriate, and strengthen motivation for engaging in the home program and other daily activities. The week 3 appointment includes symptom reassessment to evaluate interim changes. Significant deterioration at this point could indicate a need for in-person reassessment or referral to other providers . PostintPreintervention assessment is conducted through a clinical interview with youth and their parents during the first appointment and is used to inform home program prescription. Assessment is repeated in week 6 to evaluate postintervention changes.Assessment is intentionally targeted to ensure clinical application. It includes clinical history of injury details and factors known to affect recovery , selThe Tele-AR intervention comprises the following components: (1) aerobic exercise, (2) sport coordination drills, and (3) comprehensive concussion education and support. Components are individually tailored to the specific needs of each participant. The exercise program is prescribed for 3 days per week to promote compliance by minimizing disruption to daily activities and to allow for comparison between days with and without exercise. Imhoff et al  showed tJust feeling a strain) on the Pictorial Children’s Effort Rating Table (PCERT) [Safety section); the time to symptom exacerbation becomes the new target duration. Exercise duration and intensity are progressed during weekly appointments if symptoms are well tolerated, following the standardized protocol presented in After initial assessment, each participant is prescribed aerobic exercise beginning with 10 minutes of low-intensity activity at level 4 ( (PCERT) . AerobicThe initial aerobic prescription  is based on the time to symptom exacerbation reported by Gagnon et al  and DobnCoordination drills are individualized based on participant interests and preintervention assessments. They may target balance, coordination, sport-specific skills, or general health exercises. For example, a basketball player may be given shooting drills first performed stationary and progressed to include dynamic movement. Coordination exercises are performed for up to 10 minutes at the same intensity as the aerobic component and are also terminated at the onset of any new or worsening symptoms. Participants are provided with written instructions outlining the details of their home exercise program.Concussion & You self-management program [Concussion & You education handbook [Individualized education and support regarding symptom management and return to activity are provided to participants throughout the intervention. The education curriculum is based on the evidence-supported  program , which chandbook  to consoAppointments in the Tele-AR intervention are conducted through real-time videoconferencing using a secure platform that meets health privacy standards and allows for collaboration features such as screen sharing. The clinician uses a standard laptop or desktop computer, and participants may engage in the videoconferencing appointments using a computer, tablet, or smartphone.Videoconferencing is believed to facilitate therapeutic rapport and is the most common method of communication in telerehabilitation for children . Mental Special attention must be paid to ensure safety in telehealth interventions. Safety considerations for the Tele-AR intervention are summarized in Education regarding activity-related symptom exacerbation and the appropriate response is provided during program prescription. Evidence suggests that activity-related symptom exacerbations are transient and not detrimental to recovery . ExercisSymptom exacerbation considerationsEducation regarding activity-related symptom exacerbation and appropriate responseParticipants instructed to terminate exercise and rest upon significant symptom exacerbation Suspension of exercise program pending medical clearance if symptom exacerbation occurs during 3 consecutive sessions despite exercise modificationParticipants instructed to contact the research team in the event of exercise-induced symptom exacerbation that does not subside within 24 hours of rest or exercise-induced symptom exacerbation during consecutive exercise sessionsExercise safety considerationsPreparticipation screening of contraindications to exerciseEnsuring an open space for exercise free from tripping hazardsAdvising on use of support for balance (if needed)Considering parental supervision during exercise sessionsGeneral telehealth considerationsConfirming participant location, emergency contact information, and alternative methods of communication before appointment commencementDevelopment of safety protocol in case of acute medical or mental health emergencyIn this paper, we describe the development and theoretical foundation of the Tele-AR intervention for youth with concussion, specifically designed for remote service delivery. Development was guided by the MRC framework for complex interventions, involving the integration of existing evidence with appropriate theory . AlthougThe Tele-AR intervention builds on previous work advocating for a holistic approach to concussion care that emphasizes function and general well-being . It is aThe logic model presented here requires further study. Evaluating changes in identified biopsychosocial constructs may improve clinical delivery of active rehabilitation. Continued efforts to reconceptualize recovery from concussion through a biopsychosocial lens with an emphasis on function and participation may also identify new targets for change in rehabilitation and inform a stronger theoretical framework . The quaThe development process involved extensive review of the literature to integrate current evidence. However, the literature review methodology was not systematic and thus may be subject to selection bias or missed publications. In addition, most of the literature was reviewed before the COVID-19 pandemic when telehealth use and scholarship rapidly increased. Given the breadth of active rehabilitation approaches described in the literature and rapid growth of research in this field, future work using a more intentional review methodology and original investigation is warranted to determine optimal intervention approaches. All studies identified in the review implemented individual interventions. Group interventions may foster a greater sense of relatedness and social support and should be explored in this population.Tele-AR complements ongoing telemedicine initiatives to improve access to concussion care  and may


R2 ≥ 0.991), the limit of quantification (2–5 ng/mL), precision (RSD <8.12%), and accuracy (89.78–112.16%). A total of 6 AAs and 2 lignans were quantified for their content in 15 AR samples. The content of AA-IVa, AA-VIIa, and aristololactam I (AL-I) was much higher than the AA-I controlled by pharmacopoeia. Considering the potential toxicity of AAs, AA-IVa, AA-VIIa, and AL-I should also be controlled in AR. A considerable amount of active sesamin was detected in AR, suggesting that it could be added as a quality marker for the quality control of AR. The newly developed analytical method could be applied for the fast evaluation of toxic AA's content and quality during quality control of AR or preparations containing AR.Asari Radix et Rhizoma (AR) is a widely-used Chinese herbal medicine containing multiple active lignans and rare nephrotoxic components-aristolochic acids derivatives (AAs). However, the current quality control method carried out by Chinese Pharmacopoeia has defects in trace AAs detection and insufficient marker ingredients, which is unable to comprehensively evaluate the efficacy and safety of AR. To improve the quality control method of AR, a rapid, sensitive, and reliable chromatographic analytic method based on ultra-high-performance liquid chromatography-triple quadrupole tandem mass spectrometry (UHPLC-QqQ-MS) was established for the simultaneous analysis of multiple AAs and lignans in AR samples. Positive electrospray ionization mode with multiple reaction monitoring (MRM) was applied for the detection of the eight analytes. The method showed available linearity ( Asarum heterotropoides Fr. Schmidt var. mandshuricum (Maxim.) Kitag, Asarum sieboldii Miq. var. seoulense Nakai, or Asarum sieboldii Miq. More than 40 kinds of traditional Chinese patent medicines and prescriptions have used AR for the treatment of cold, headache, toothache, runny nose, rhinorrhea, rheumatism, and cough with phlegm retention. In the existing quality control standards, asarinin and aristolochic acid I were approved as indicating ingredients of AR [Asari Radix et Rhizoma (AR) is the roots and rhizomes of ts of AR  due to tts of AR  and potets of AR , separatAristolochia debilis, Aristolochia manshuriensis, Aristolochiae fangchi, and Aristolochia contorta were banned and restricted for their medicinal use by the British Committee on the Safety of Medication and the U.S. Food and Drug Administration successively [As a plant of the Aristolochiaceae, the possible risk of aristolochic acid nephropathy caused by herbal medicine will naturally arouse vigilance. Aristolochic acid derivatives (AAs) are the culprits of aristolochic acid nephropathy reported since the late 20th century . Plants essively . The safessively . In addiessively –10. As aessively , 12 are essively –16. The Asarinin and sesamin, the major ingredients pertaining to the lignan phytochemical group in AR, have a variety of pharmacological activities consistent with the efficacy of AR, including antipyretic, antiinflammatory, and immunosuppressive effects , 17–23. Until now, a variety of qualitative analyses and quantitative determination of AR components have been developed, including high-performance liquid chromatography (HPLC) coupled to photodiode array detection –29, fluoAlthough the content of AAs in AR is negligible, consumers can still purchase AR with uncertified sources from a number of websites. Moreover, AR whole plants are habitually used in some districts, which contain higher AAs than roots and rhizomes . These uReference standards AA-I, AA-III, AA-IVa, and asarinin were purchased from Chengdu Aifa Biotechnology Co., Ltd., AA-II, AA-VIIa, and AL-I were purchased from Shanghai Hongyong Biotechnology Co., Ltd., sesamin was purchased from Shanghai Yuanye Biotechnology Co., Ltd. HPLC-grade methanol, acetonitrile, and formic acid were purchased from Fisher Scientific Co. . Deionized water was purified using a Milli-Q Academic System made by Millipore Co. . All other chemicals were of analytical grade.Asarum heterotropoides Fr. Schmidt var. mandshuricum (Maxim.) Kitag authenticated by Prof. Lihong Wu . The voucher specimens were deposited in the specimen room of the Shanghai Standardization Research Center for Traditional Chinese Medicine.Samples of AR were collected from Liaoning province or purchased from Bozhou Traditional Chinese Medicine Market. Their supplementary information was listed in μm) at 40°C. The mobile phase consisted of water containing 0.1% formic acid (A) and acetonitrile (B) with gradient elution programmed as follows: 0–2 min, 10%–45% B; 2–6 min, 45%–60% B; 6-7 min, 95% B; 7-8 min, 10% B. The flow rate was kept at 0.4 mL/min, and 5 µL of standard and sample solution were injected in each run.The UHPLC-QqQ-MS analysis was performed on an Agilent 1290-UHPLC system  coupled with an Agilent 6410 Triple Quad liquid chromatography-tandem mass spectrometry system  at positive ion mode as the quantitative analysis instrument. The separation was run on the ACQUITY UPLC BEH C18 column  were independently prepared by dissolving in an appropriate amount of methanol and stored at −20°C. An appropriate amount of standard stock solutions were mixed and diluted by methanol to get a mixed standard stock solution at a final concentration of 10 μg/mL for AAs and 100 μg/mL for asarinin and sesamin. The working solutions were prepared by the dilution of standard stock solutions to obtain the required concentrations for the method validation . The calibration standard solutions of eight concentration levels  were prepared by diluting the above stock solutions. All these solutions were stored at 4°C in a refrigerator.Eight standard stock solutions  were accurately weighed and extracted by ultrasonic  with 15 mL 70% methanol for 45 min. The extract was cooled down to room temperature and compensated by weight with 70% methanol. The solution was centrifuged at 3000 rpm for 5 min, then the supernatants were filtered with a 0.22 Calibration curves were prepared with the working solutions as described in µL. The LOD was defined as the concentration for which the signal-to-noise (S/N) of 10 was obtained.The stock solutions of eight reference compounds were diluted to a range of 2–50 ng/mL. The injection volume was 5 n = 3) were added to the herb. At last, the herb was extracted and analyzed as described in The precisions were evaluated by the analysis of six injections of working solutions at four concentrations, that is, 5, 20, 100, and 750 ng/mL for each AAs standard and 50, 200, 1000, and 7500 ng/mL for asarinin and sesamin. The LLOQ of the assay was quantitated using accuracy within 20% bias of the nominal concentration and relative standard deviation not exceeding 20%. Six different sample solutions prepared from the same sample were analyzed to confirm the repeatability of the developed method. The stability of the sample was tested by injecting the same amount of sample preparation at 0, 2, 4, 6, 8, 10, 12, 16, 24, and 48 h stored in a sample plate at 10°C. The peak area of the stability samples was substituted into the calibration curve to calculate the concentration of the analytes. The RSD value of the concentration of each analyte was then calculated to obtain the stability and repeatability results. The recovery was used to evaluate the accuracy of the method. For the recovery testing, approximately 0.5 g of the fine powder of sample no. 6 was accurately weighted, then accurate amounts of mixed standards +, and (M + H-H2O)+ were the basic protonated ions for eight analytes under positive ion mode. Base peak with the highest response was selected as precursor ion for AA-I, AA-II, AA-III, AA-VIIa, AL-I, asarinin and sesamin, except for AA-Iva selected (M + H-NO2)+ as precursor ion to distinguish from AA-VIIa. Then, the conditions of multiple reaction monitoring (MRM) determination, including fragmentor, collision energy, and cell accelerating voltage, were optimized according to the highest sensitivity and specific ion pairs. The MRM transitions and parameters of sesquiterpene lactone compounds are shown in For optimization of MS conditions, the full-scan MS method was used to examine the target analytes in positive ionization mode. All the compounds were then determined, respectively, in direct infusion mode to optimize a proper transition for the MS/MS detection. (M+H)R2) ranging from 0.9912 to 0.9989 for eight analytes within the linear ranges, indicating its feasibility for quantification.The eight-point calibration curves of eight analytes  showed available linearity ranging from 5 to 1000 ng/mL (sesamin and asarinin ranging from 50 to 10000 ng/mL) by analyzing standard working solutions at eight concentrations, and the typical equations of the calibration curves are shown in The LOQ of each analyte  was 2, 2, 5, 5, 2, 2, 50, and 50 ng/mL, respectively, demonstrating the good sensitivity of the established method.Repeatability and sample stability were evaluated by the relative standard deviation (RSD) values presented in The precision of eight analytes  at four levels was within 8.12%, and the accuracy of the eight analytes ranged from 89.78% to 112.16%, which were within the acceptable limits. All data of precision and accuracy were summarized in As summarized in μg/g, respectively. AA-II and AA-III were not detected in any sample. The total content of all AAs detected was 26.83 μg/g on average. All AR samples meet the standards of marker ingredient AA-I  and asarinin  in the Chinese pharmacopoeia [μg/g, which is far below the upper limit of 10 μg/g. The lowest content of asarinin is 995.88 μg/g, which is about twice the folds of the lower limit. Among other AAs derivatives, a considerable amount of AA-VIIa, AA-IVa, and AL-I were detected in all AR samples and showed a higher content than AA-I (0.64 μg/g), with an average content of 4.86, 9.28, and 12.06 μg/g, respectively. At the same time, a considerable amount of sesamin with an average content of 659.00 μg/g was found. The obtained results provided a reference for the profile of the lignans and AAs presented in AR, which would be beneficial for quality control of AR in the future.Using the developed UHPLC-QqQ-MS method, quantitation of AA-I, AA-IVa, AA-VIIa, AL-I, asarinin, and sesamin in 15 batches of AR samples was carried out. The typical MRM chromatograms of standard solution and sample solution were shown in For the analysis of AAs, researchers focus on developing FLD  or MS 3 detectorin vitro [Salmonella strains and nontoxic to LLC-PK1 cells [In vivo, AA-I showed the strongest nephrotoxicity in mice; AA-II has mild nephrotoxicity; AA-IVa and AL-I do not cause blood chemistry or tissue abnormalities of the kidneys, as indicated by the academic changes [With regards to the toxicity of AAs derivatives, early reports have believed that AA-I and AA-II are the major toxic components among AAs –40. AccoK1 cells , yet pro changes . However changes –45. Alth changes , 15. Mor changes . RelatedFrom the perspective of quality control, safety and effectiveness are the key factors in controlling the quality of medicinal materials. In this study, the potential toxic AAs were detected in all 15 AR samples, among which marker ingredient AA-I accounted for only 2.38% of the total AAs on average. In order to ensure the safety of AR more accurately, the limitation of the total number of AAs is a proposal worth considering. More nephrotoxicity-related evaluation studies are still required to clarify the specific upper limit of AAs. In addition, a considerable amount of sesamin was also found in each sample. In view of the similar pharmacological activities of sesamin and the existing quality marker asarinin, it is recommended to add sesamin as the quality marker in the following quality standard of AR.In conclusion, a rapid and sensitive UHPLC-QqQ-MS method was established for the simultaneous quantification of six aristolochic acids and two lignans in AR, which was validated with good accuracy and precision. AA-I, AA-IVa, AA-VIIa, AL-I, asarinin, and sesamin were detected in all 15 AR samples by the developed method, and their content was clarified. The content of AA-IVa, AA-VIIa, and AL-I was much higher than AA-I in all AR samples, indicating that AA-IVa, AA-VIIa, and AL-I should be limited together to a certain extent for the safety use of AR. Active ingredient sesamin is also recommended to be added as a quality marker for the improvement of quality control of AR. The newly developed analytical method could be applied for the fast evaluation of toxic AAs content and quality during quality control of AR commercial medicinal materials or the preparations of AR contained.


The intervention was a standard vestibular rehabilitation, with or without ABF, for 45 min biweekly for 6 weeks. The ABF intervention involved a smartphone that provided auditory feedback when postural sway was outside of predetermined equilibrium parameters. Participant's completed the Post-Concussion Symptom Scale (PCSS). Balance was assessed with the sensory organization test (SOT) and the Central Sensorimotor Integration test which measured sensory weighting, motor activation, and time delay with sway evoked by surface and/or visual surround tilts. Effect sizes (Hedge's G) were calculated on the change between pre-and post-rehabilitation scores. Both groups demonstrated similar medium effect-sized decreases in PCSS and large increases in SOT composite scores after rehabilitation. Effect sizes were minimal for increasing sensory weighting for both groups. The with ABF group showed a trend of larger effect sizes in increasing motor activation  and in decreasing time delay  relative to the without ABF group. Current clinical practice focuses primarily on sensory weighting. However, the evaluation and utilization of motor activation factors in vestibular rehabilitation, potentially with ABF, may provide a more complete assessment of recovery and improve outcomes.Complaints of non-resolving imbalance are common in individuals with chronic mild traumatic brain injury (mTBI). Vestibular rehabilitation therapy may be beneficial for this population. Additionally, wearable sensors can enable biofeedback, specifically audio biofeedback (ABF), and aid in retraining balance control mechanisms in people with balance impairments. In this study, we described the effectiveness of vestibular rehabilitation therapy with and without ABF to improve balance in people with chronic mTBI. Participants ( Symptoms following a mild traumatic brain injury (mTBI) that persist for months after the initial injury can directly impact quality of life –3. ComplVestibular rehabilitation is an emerging treatment option for persistent imbalance and dizziness symptoms after mTBI –16. ReceA novel and emerging approach to vestibular rehabilitation is using biofeedback –23. BiofGiven the potential benefit to enhance rehabilitation of imbalance in the chronic mTBI population through the addition of biofeedback during training, this study sought to explore the effects of augmenting vestibular rehabilitation with ABF relative to a standard vestibular rehabilitation program without ABF. We hypothesized that the addition of ABF would enhance the effectiveness of a standard vestibular rehabilitation program by reducing symptoms and improving balance control.n = 40) participated in the study. Demographic details are given in All study participants provided written informed consent and the Oregon Health & Science University and Veterans Affairs Portland Health Care System joint Institutional Review Board approved recruitment procedures and experimental protocols. People who sustained an mTBI >3 months prior and reported continued imbalance (Participants in our larger study (NCT02748109) who qualified and were interested in rehabilitation for their symptoms were randomized to either vestibular rehabilitation with ABF or vestibular rehabilitation only (without ABF). Randomization occurred after enrollment and pre-rehabilitation assessments. Vestibular rehabilitation consisted of biweekly sessions for 6 weeks and included a warm-up with 5 min of walking, followed by 20 min of static balance exercises, and 20 min of dynamic balance exercises . Each exParticipants randomized to the ABF intervention wore a pair of headphones and a smartphone  that was placed on the subject's back at L4/5 for static balance exercises and was raised to T7/8 for dynamic balance exercises during exercises at the rehabilitation sessions . The smaAll participants provided baseline demographic information  and completed questionnaires on post-mTBI symptom severity , and on overall impact of dizziness on daily life (Dizziness Handicap Inventory—DHI). The PCSS assessed the severity of 22 concussion symptoms on a scale ranging from 0 (none) to 6 (very severe). The PCSS total symptom severity scores range from 0 (best) to 132 (worst). The DHI is a 25 item questionnaire that assessed the overall impact of dizziness on daily life , 30. ParAs part of the broader test battery, participants were evaluated on the sensory organization test (SOT) and a custom Central Sensorimotor Integration (CSMI) test pre- and post-rehabilitation , 32. BotAll outcome measures of the CSMI test are obtained by a custom analysis applied to data recorded on a NeuroCom SMART Balance Master platform which had been modified to provide a higher contrast visual scene and to deliver low-amplitude (2° peak-to-peak) pseudorandom stimuli consisting of 12 continuously repeated 20-s duration cycles of wide bandwidth support surface-tilt and/or visual surround-tilt stimuli . SimilarA detailed description of the analysis of CSMI tests is provided elsewhere , 32 but The primary outcome measures of the CSMI test are parameters of a balance control model that account for the experimental FRF derived from the analysis of CoM sway evoked by the pseudorandom stimuli. The parameters included sensory weights, time delay, and motor activation factors. The sensory weights represent the relative contributions of proprioceptive, visual, and vestibular sensory information used for balance control such that, in each of the 4 test conditions, the sum of weights equaled 1. The time delay quantified the overall feedback delay due to neural transmission, central processing for sensory integration and motor command generation, and muscle activation. Motor activation is represented by two components (stiffness and damping factors) that determined how much corrective ankle joint torque was generated proportional to the sensory-derived internal estimate of body sway angular position and angular velocity, respectively. Stiffness and damping factors were normalized by dividing by the product of body mass, constant of gravitation, and CoM height to account for the high correlation of stiffness and damping factors with body mechanics .In addition to the balance control model parameters, we also calculated sway outcome measures of balance that included (1) the root mean squared (RMS) value of stimulus-evoked CoM sway, which is the RMS value of the zero-meaned, cycle-averaged, stimulus-evoked CoM sway angle data from the final 11 cycles of the pseudorandom stimulus, (2) the RMS value of the “remnant CoM sway” which is the square root of the sway variance that is not accounted for by the cycle-averaged sway response to the stimulus , 34, andThe with and without ABF group baseline demographic characteristics were compared with parametric and non-parametric group difference analyses. The outcome measures included the PCSS, DHI, and SOT composite scores, the model-derived parameters of the CSMI test , and CSMI sway-derived measures of balance performance. We limited analysis of the model-derived and sway-derived parameters of CSMI to conditions that directly evaluated vestibular weighting—SS/EC and SS + VS/EO conditions.To describe the effects of augmenting rehabilitation with ABF on assessments of mTBI-symptoms and balance function, we calculated the effect size of the change between pre-and post-rehabilitation outcomes (Hedge's G) using the Measures of Effect Size (MES) Toolbox in MATLAB 2021b . Additionally, we determined the number of participants that did and did not change their SOT composite score beyond a previously established minimal detectable change (MDC) score of 8 . Effect n = 1), an unrelated rehabilitation musculoskeletal injury (n = 1), time constraints (n = 3), subject withdrawal due to randomized group assignment (n = 1), personal reasons (n = 1), and loss to follow up without communication (n = 2). A total of 40 participants were enrolled and randomized for vestibular rehabilitation (20 with ABF and 20 without ABF) with 31 participants completing the rehabilitation and post-rehabilitation assessments (16 with ABF and 15 without ABF). Nine participants did not complete post-rehabilitation testing due to: pregnancy during the rehabilitation (t(22) = 0.56, p = 0.491). At the start of the intervention, participants in the without ABF and with ABF groups completed 29 and 32% of the exercises in the rehabilitation program, respectively. By the end of the intervention, participants in the without ABF and with ABF groups completed 65% and 60% of the exercises. However, both groups progressed similarly as indicated by the change in the percentage of the exercises completed over the intervention .There were no significant group differences (with ABF and without ABF) on demographics, days since injury, pre-rehabilitation DHI, rehabilitation adherence, and home exercise adherence . HoweverVarious trends emerged when comparing the rehabilitation groups with and without ABF. Both the with and without ABF groups had similar medium effect sizes in decreased PCSS total symptom severity scores . HoweverThere were group-dependent trends in the magnitudes of effect sizes for the CSMI model-derived parameters and sway-derived outcomes. The group without ABF had small effects on changes in vestibular weighting, while the group with ABF had no effects . However, this study was an exploratory aim of a larger study aimed at assessing central sensory impairments in people with chronic mTBI symptoms . Our datAnother limitation is that our results focused on static balance performance. Therefore, the effects of vestibular rehabilitation with and without ABF on dynamic balance  remain unknown. There are differences in the physiological mechanisms required for standing balance and dynamic balance. Therefore, future work should explore the effectiveness of rehabilitation with and without ABF on dynamic balance since dynamic balance is particularly relevant for daily life function and navigating in the real world. Lastly, although we observed consistent and large improvements in symptom severity and some aspects of sensory integration, our research protocol of biweekly sessions does not reflect current clinical practice. Patients are typically only seen by a therapist once or twice and are expected to perform exercises at home without supervision. Future studies should investigate dose-response parameters to determine optimal scheduling of therapy.Vestibular rehabilitation augmented with and without ABF was able to decrease persistent post-mTBI symptom severity in people on average a year from their initial mTBI. Additionally, both rehabilitation with and without ABF improved balance function when measured with the SOT. However, larger improvements in time delay and motor activation components of balance function were observed for people completing vestibular rehabilitation augmented with ABF. These preliminary results suggest additional approaches such as neuromuscular training and real-time biofeedback should be considered for rehabilitation after mTBI.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Oregon Health and Science University and Veterans Affairs Portland Health Care System joint Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.LK and RP contributed to the conception and design of this study. KC, LP, PF, and RP contributed to data acquisition. JW and NP provided subject rehabilitation. KC, LK, LP, PF, and RP contributed to analysis and interpretation of data. KC, RP, JW, NC, and PF wrote the first draft of the manuscript. All authors contributed to the manuscript revision, read, and approved the submitted version.This work was supported by the Assistant Secretary of Defense for Health Affairs (Award Nos. W81XWH-15-1-0620 and W81XWH-17-1-0424).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.