UNASSIGNED: This study aimed to assess metal sensitization ranges among orthopaedic patients by comparing adaptive immune responses in all-comer pre- and post-operative orthopaedic adults who were COVID-19 unvaccinated or vaccinated vs patients with a painful aseptic implant by lymphocyte transformation test (LTT) to SARS-CoV-2-Spike-Protein (SP) and implant metal(s), respectively.
UNASSIGNED: Data were retrospectively reviewed from three independent groups: unvaccinated COVID-19 adults (n = 23); fully COVID-19 vaccinated adults (n = 35); unvaccinated, painful aseptic implant patients with history of metal allergy (n = 98). Standard in vitro LTT for SP and implant metal(s) (nickel, cobalt) were performed and rated as negative (stimulation index [SI]<2), mild (SI ≥ 2), positive (SI ≥ 4-15), and high sensitization (SI > 15) adaptive immune responses to tested antigen.
UNASSIGNED: Overall, 17/23 (74%) of unvaccinated adults showed negative to mild LTT ranges, and 35/35 (100%) of vaccinated showed mild to positive LTT ranges to SP. Vaccinated individuals showed significantly higher median SI (16.1) to SP than unvaccinated (median SI, 1.7; P < 0.0001). Most vaccinated adults (94%) showed a lymphocyte SI > 4 to SP, establishing LTT SI ≥ 4 with >90% sensitivity for diagnosing effective COVID-19 adaptive immune responses. Significantly fewer painful orthopaedic patients (41%) showed comparable elevated levels of lymphocyte metal sensitivity at SI ≥ 4 compared to vaccinated group (P < 0.0001).
UNASSIGNED: Vaccinated adults showed significantly higher lymphocyte SI to SP than unvaccinated indicating that SI ranges ≥4 should be set as unequivocally diagnostic of LTT-positive adaptive immune responses to tested antigen. This analysis supports using higher LTT SI ranges (SI ≥ 4) in diagnosing clinical orthopaedic-related Type IV metal-hypersensitivity responses among orthopaedic patients.

BACKGROUND: Arthroscopically assisted lower trapezius tendon (aLTT) transfer is one of the treatment options for posterior-superior irreparable rotator cuff tears (PSIRCTs). Although short-term clinical outcomes have shown promising results, there are currently no reported clinical outcomes over a longer follow-up period. This study evaluated the mid-term outcomes of aLTT transfer in patients with a diagnosis of PSIRCT.
METHODS: This retrospective case-series study included patients who underwent aLTT transfer between May 2017 and May 2019. The clinical outcome assessment included the visual analog scale (VAS) pain score, Constant score, American Shoulder and Elbow Surgeons score, University of California-Los Angeles score, Activities of Daily Living Requiring Active External Rotation (ADLER) score, active range of motion, Single Assessment Numeric Evaluation score, and return-to-work rate. The radiographic analysis included the acromiohumeral distance, Hamada grade, and integrity of the transferred tendon at final follow-up. Subgroup analyses were performed based on the integrity of the transferred tendon and the trophicity of the teres minor (Tm).
RESULTS: This study enrolled 36 patients with a mean age of 63.4 years who met the inclusion criteria and were followed up for a mean of 58.2 ± 5.3 months. At final follow-up, the patients showed significant improvement in mean VAS score, Constant score, American Shoulder and Elbow Surgeons score, University of California-Los Angeles score, ADLER score, and active range of motion in all directions except internal rotation. A decrease in the acromiohumeral distance and an increase in the Hamada grade were observed at final follow-up (P = .040 and P = .006, respectively). Retears of the transferred tendon occurred in 7 patients, and postoperative infections developed in 2 individuals. An interesting finding was that the retear group still demonstrated improvement in the VAS score but did not show improvement in external rotation at the side by the final follow-up. Compared with the Tm non-hypertrophy group, the Tm hypertrophy group showed significantly better improvement in external rotation at 90° of abduction and at the side, as well as the ADLER score. Of the study patients, 30 (83.3%) were able to successfully resume their previous work.
CONCLUSIONS: In this study, aLTT transfer in patients with PSIRCTs demonstrated significant improvements in clinical and radiologic outcomes by the final follow-up. These findings provide support for the mid-term safety and effectiveness of aLTT transfer as a viable joint-preserving treatment option for PSIRCTs. However, larger and longer-term studies are still needed to further validate these findings.

In the first wave of COVID-19, up to 20% of patients had skin lesions with variable characteristics. There is no clear evidence of the involvement of the SARS-CoV-2 virus in all cases; some of these lesions may be secondary to drug hypersensitivity. To analyze the possible cause of the skin lesions, we performed a complete allergology study on 11 patients. One year after recovery from COVID-19, we performed a lymphocyte transformation test (LTT) and Th1/Th2 cytokine secretion assays for PBMCs. We included five nonallergic patients treated with the same drugs without lesions. Except for one patient who had an immediate reaction to azithromycin, all patients had a positive LTT result for at least one of the drugs tested (azithromycin, clavulanic acid, hydroxychloroquine, lopinavir, and ritonavir). None of the nonallergic patients had a positive LTT result. We found mixed Th1/Th2 cytokine secretion (IL-4, IL-5, IL-13, and IFN-γ) in patients with skin lesions corresponding to mixed drug hypersensitivity type IVa and IVb. In all cases, we identified a candidate drug as the culprit for skin lesions during SARS-CoV-2 infection, although only three patients had a positive drug challenge. Therefore, it would be reasonable to recommend avoiding the drug in question in all cases.

Coronavirus (COVID-19) vaccines have proved to be effective in the pandemic response but can cause adverse events such as delayed hypersensitivity reactions (DHRs). Delayed-reading intradermal tests (IDT) to vaccines are limited by false-positive results and may reflect a cell-mediated rather than IgE-mediated immune response. Lymphocyte transformation test (LTT), which has been utilized in the diagnosis of drug allergy, may be helpful in suspected COVID-19 vaccine and/or its excipient-related DHRs. To investigate the use of LTT in two suspected cases of COVID-19 vaccine-induced DHRs, two patients with suspected DHRs to COVID-19 vaccination were tested by delayed-reading IDT and LTT against vaccines and their excipients. A 47-year-old man developed acute mixed-pattern hepatitis after the second dose of ChAdOx1 vaccine. LTT performed at 2 months post-vaccination revealed reactivity to the ChAdOx1 vaccine, polysorbate 80 and mildly to PEG 2050 but not BNT162b2 vaccine. Delayed-reading IDT returned negative to both vaccines and excipients. He tolerated BNT162b2 vaccination with no adverse events. A 36-year-old woman presented with subacute morbilliform eruption and hepatitis after the first dose of BNT162b2 vaccine. LTT performed 3 months later revealed reactivity to the BNT162b2 but not PEG 2050. Repeat LTT following subsequent natural Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) infection revealed reactivity to ChAdOx1 and NVX-CoV2373 vaccines but not polysorbate 80. Delayed-reading IDT remained negative. She proceeded with NVX-CoV2373 vaccination with no symptom recurrence. LTT may be a useful tool in suspected COVID-19 vaccine-related DHRs. Further evaluation with a larger patient cohort is required.

There is currently a lack of guidelines for clinicians regarding titanium hypersensitivity in implant dentistry. Diagnostic tests such as the epicutaneous test or the lymphocyte transformation test showed inconsistent results regarding reliability and validity and thus, evidence-based consensus recommendations regarding diagnostic and therapeutic options may be helpful in clinical decision-making. Therefore, the German S3 guideline on titanium hypersensitivity in implant dentistry was developed.
In the objectives, procedure, voting method and venue were defined and the consensus participants were invited. A systematic literature research was performed, and the overall quality of the evidence was rated according to the GRADE working group. Eight recommendations were formulated within the framework of a structured consensus conference under independent moderation and could be voted on with strong consensus (> 95% agreement). The formulated statements and recommendations were developed in small groups according to the guidelines of the Association of the Scientific Medical Societies in Germany (AWMF) and were discussed and agreed upon in the plenum.
For reasonable decision-making, a patient\'s clinical symptoms should be regarded as leading parameters, which are usually expressed by a local inflammatory reaction with subsequent disturbed osseous integration. Allergy tests, such as the epicutaneous test or the lymphocyte transformation test are not helpful in titanium intolerance assessments, since these tests indicate T cell-mediated allergies, which are not observed in titanium intolerance reactions. Other metals and impurities that might be present in superstructures or alloys also need to be considered as the cause of an intolerance reaction and a trigger for contact sensitization. In the case of a suspected titanium particle-related, local immunologically induced inflammatory reaction with subsequent impaired osseous integration, dental ceramic implants can be considered as a therapeutic option.

LTT is a life-threatening incident that is fortunately rare. The presenting symptoms might not correlate with the intensity of trauma and range from mild endolaryngeal edema to complete laryngotracheal transection. An early diagnosis and timely intervention is required for successful outcomes and minimizing complications. This retrospective audit was performed on 18 patients of LTT who presented to the emergency from January 2017 to December 2019. The history, clinical presentation, examination findings, degree and nature of trauma, diagnostic modalities, medical and surgical management, and outcomes were analyzed. A total of 13 males and 5 females were included in this audit, with a mean age of 38.7 years. The most common cause was accidental in 77.7% patients. 61.5% of patients presented with Schaefer grade 3 and higher. Out of which 46% underwent emergent neck exploration and repair. 27.7% (5/18) presented with sequelae which were managed either by T- tube stenting, endoscopic dilatation by coblation, or laryngotracheal resection (LTR) and end-to-end anastomosis (EEA). Out of 14 surgically reconstructed airways, successful decannulation was achieved in 57.1% (8) patients. High clinical suspicion, early referral with emergent intervention is paramount for successful outcomes, fewer recurrences, and reduction of hospital\'s and patient\'s financial burden as timely planning and intervention can ensure successful decannulation of around two thirds of the higher grades (grade 3-5) of laryngotracheal traumatic injuries. Early airway establishment is the most critical goal. Definitive treatment protocols are needed in this field which warrants further formulation of multicentric studies and audits.

BACKGROUND: The lymphocyte transformation test (LTT) is an in vitro assay used to diagnose drug induced hypersensitivity reactions by detecting the activation and expansion of drug-specific memory T cells to the suspected implicated drug. Traditionally radiolabelled thymidine (3H-thymidine) has been used but requires the handling and disposal of radioactive materials.
OBJECTIVE: To examine safe alternatives to 3H-thymidine, test assay modifications for improved assay sensitivity and evaluate the modified LTT in patients with DRESS and AGEP.
METHODS: Four proliferation detection assays (BRDU, CyQUANT™, MTT and XTT) were screened for LTT sensitivity. XTT the most sensitive and practical was selected for further evaluation Modifications like autologous serum (AS) and regulatory T cell depletion (T-REG) were tested for improved assay sensitivity. Finally, an initial evaluation of the XTT-LTT was performed in 8 patients with DRESS and 2 with AGEP including cytokine testing.
RESULTS: Of the non-radioactive alternatives we tested, XTT a colorimetric assay was the most sensitive and practical to move to evaluation. The addition of AS increased background signal. Depletion of T-REGs improved sensitivity but cell sorting time and risk of contamination limited benefit. Of eight patients diagnosed with DRESS and 2 with AGEP tested with XTT-LTT assay results showed our assay matched clinical findings of implicated drugs in 8/10 patients when using a stimulation index (SI) ≥ 2 and 8/10 with analysis by ANOVA. All ten patients were correctly diagnosed by either analysis.
CONCLUSIONS: XTT appears to be a safe, viable alternative to 3H-thymidine, with high sensitivity and allowing direct cytokine quantification on specific patient cells.

Ligand targeted therapy (LTT) is a precision medicine strategy that can selectively target diseased cells while minimizing off-target effects on healthy cells. Integrin-targeted LTT has been developed recently for angiogenesis-related diseases. However, the clinical success is based on the optimal design of the nanoparticles for inducing receptor clustering within the cell membrane. The current study focused on determining the surface density of Ser-Asp-Val containing anti-integrin heptapeptide on poly (ethylene glycol)-b-poly(propylene sulfide) micelles (MC) required for anti-angiogenic effects on HUVECs. Varying peptide density on PEG-b-PPS/Pep-PA MCs (Pep-PA-Peptide-palmitoleic acid) was used in comparison to a random peptide (SGV) and cRGD (cyclic-Arginine-Glycine-Aspartic acid) construct at 5%-density on MCs. Immunocytochemistry using CD51/CD31 antibody was performed to study the integrin blocking by MCs. In addition, the expression of VWF and PECAM-1, cell migration and tube formation was evaluated in the presence of PEG-b-PPS/Pep-PA MCs. The results show PEG-b-PPS/SDV-PA MCs with 5%-peptide density to achieve significantly higher αvβ3 blocking compared to random peptide as well as cRGD. In addition, αvβ3 blocking via MCs further reduced the expression of vWF and PECAM-1 angiogenesis protein expression in HUVECs. Although a significant level of integrin blocking was observed for 1%-peptide density on MCs, the cell migration and tube formation were not significantly affected. In conclusion, the results of this study demonstrate that the peptide surface density on PEG-b-PPS/Pep-PA MCs has a significant impact in integrin blocking as well as inhibiting angiogenesis during LTT. The outcomes of this study provides insight into the design of ligand targeted nanocarriers for various disease conditions.

There are rising concerns about titanium hypersensitivity reaction regarding dental endosseous implants. This review aims to summarize and compare the validity and reliability of the available dermatological and laboratory diagnostic tests regarding titanium hypersensitivity. The following PICO design was used: In Patients with titanium dental implants (P) does epicutaneous testing (ECT) (I), compared to lymphocyte transformation test (LTT) or Memory Lymphocyte Immunostimulation Assay (MELISA) (C) detect hypersensitivity reactions (O)? A literature search was performed including all studies dealing with this topic. Studies regarding orthopedic implants were excluded.
Three databases (MEDLINE PubMed, Cochrane Library, SciELO) were screened for suitable studies and an additional manual search was also performed. Literature regarding hypersensitivity reactions in orthopedic implants, hypersensitivity reactions regarding implants not related to dental or maxillofacial surgery, animal studies and in vitro studies were excluded. A quality assessment of all selected full-text articles was performed. Randomized, controlled trials were evaluated with the Cochrane Risk of Bias Tool I. Cohort studies were assessed according to the New Castle-Ottawa Scale and case series according to Moga et al. (Development of a quality appraisal tool for case series studies using a modified Delphi technique. 2012).
10 studies were included in the quantitative synthesis and available for the endpoint diagnostics of intolerance reactions to titanium dental implants: 2 clinical studies, 7 cohort studies and 1 case series. The potential for bias (internal validity) for these studies was overall rated as high.
The study of the available literature regarding ECT and MELISA or LTT in patients with suspected titanium hypersensitivity showed inconsistent results in terms of reliability and validity and thus, those tests should be regarded cautiously. There is strong evidence that titanium hypersensitivity in dental implants is associated with innate immunity: unspecific pro-inflammatory responses due to particle induced hyperreactivity of macrophages or toxicological responses especially towards nanoparticles rather than activation of the adaptive immune system. Therefore, tests detecting allergies do not seem expedient and inflammatory clinical signs should be regarded as leading parameters.

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