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For a restrictive covenant to be enforceable, it generally must (1) reasonably protect a legitimate business interest of the employer, (2) be limited in scope, and (3) not violate the public interest.1 Before a court can determine whether a restrictive covenant is reasonable, it must make two threshold determinations: (1) that the covenant is ancillary to a valid contract and (2) that the covenant is supported by adequate consideration. Tortious interference with a contract requires that there is a valid contract; that the defendant knew of the contract; and that the defendant intentionally and unjustifiably caused a breach of it, resulting in damages to the plaintiff.3 Tortious interference with a business expectancy requires a reasonable expectation of entering into a valid business relationship, the defendant's knowledge of this expectation, the purposeful prevention of this legitimate expectation from coming to fruition, and damages.4 These claims are often brought against departing employees for interfering with customer relationships in violation of their noncompete agreements, as well as against the new employer for interfering with both the customer relationship and the noncompete agreement itself. \"10 Thus, courts have declined to find value in a customer list that could be obtained from the Yellow Pages or the internet,11 in a compilation of buyers at well-known retailers,12 and in pricing information that could be obtained by calling the dealer.13 Courts have found value, however, in a \"preferred customer\" list,14 in a customer list that was not readily ascertainable,15 in a customer list with individual customer preferences,16 in the names and detailed information of 1,200 customers,17 and in a list detailing the pricing differences among various customers.18 In other situations, employees may take sales manuals, pricing data, supplier information, or other information that may be a trade secret. Continued improper solicitation of clients by a former employee also gives rise to irreparable harm.23 The requirement of irreparable harm is usually satisfied in cases involving restrictive covenants because the precise amount of damages is difficult to assess.24 The effect on future profits is irreparable if the solicitations are based on word-of-mouth referrals.25 Irreparable harm may be found in the solicitation of the former employer's customers because of the associated loss of goodwill.26 The movant, however, must be able to articulate harm beyond mere lost revenue.27 Courts often understand the economic reality that once a client is lost, it is lost forever and no order of the court will bring it back.

Background The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer. Methods Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible. Results Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells. Conclusions Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.

As global vaccination campaigns against SARS-CoV-2 proceed, there is particular interest in the longevity of immune protection, especially with regard to increasingly infectious virus variants. Neutralizing antibodies (Nabs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are promising correlates of protective immunity and have been successfully used for prevention and therapy. As SARS-CoV-2 variants of concern (VOCs) are known to affect binding to the ACE2 receptor and by extension neutralizing activity, we developed a bead-based multiplex ACE2-RBD inhibition assay (RBDCoV-ACE2) as a highly scalable, time-, cost-, and material-saving alternative to infectious live-virus neutralization tests. By mimicking the interaction between ACE2 and the RBD, this serological multiplex assay allows the simultaneous analysis of ACE2 binding inhibition to the RBDs of all SARS-CoV-2 VOCs and variants of interest (VOIs) in a single well. Following validation against a classical virus neutralization test and comparison of performance against a commercially available assay, we analyzed 266 serum samples from 168 COVID-19 patients of varying severity. ACE2 binding inhibition was reduced for ten out of eleven variants examined compared to wild-type, especially for those displaying the E484K mutation such as VOCs beta and gamma. ACE2 binding inhibition, while highly individualistic, positively correlated with IgG levels. ACE2 binding inhibition also correlated with disease severity up to WHO grade 7, after which it reduced.

Background: A short-term protocol for evaluation of National Football League (NFL) athletes incurring concussion has yet to be fully defined and framed in the context of the short-term potential team and career longevity, financial risk, and performance. Purpose: To compare the short-term career outcomes for NFL players with concussions by analyzing the effect of concussions on (1) franchise release rate, (2) career length, (3) salary, and (4) performance. Study Design: Cohort study; Level of evidence, 3. Methods: NFL player transaction records and publicly available injury reports from August 2005 to January 2016 were analyzed. All players sustaining documented concussions were evaluated for a change to inactive or DNP (“did not participate”) status. A case-control design compared franchise release rates and remaining NFL career span. Career length was analyzed via survival analysis. Salary and performance differences were analyzed with publicly available contract data and a performance-scoring algorithm based on position/player level. Results: Of the 5894 eligible NFL players over the 11-year period, 307 sustained publicly reported concussions resulting in the DNP injury protocol. Analysis of the probability of remaining in the league demonstrated a statistically significantly shorter career length for the concussion group at 3 and 5 years after concussion. The year-over-year change in contract value for the concussion group resulted in a mean overall salary reduction of $300,000 ± $1,300,000 per year (interquartile range, –$723,000 to $450,000 per year). The performance score reduction for all offensive scoring players sustaining concussions was statistically significant. Conclusion: This retrospective study demonstrated that NFL players who sustain a concussion face a higher overall franchise release rate and shorter career span. Players who sustained concussions may incur significant salary reductions and perform worse after concussion. Short-term reductions in longevity, performance, and salary after concussion exist and deserve additional consideration.

We previously generated a mouse model with a mutation in the murine Atm gene that recapitulates many aspects of the childhood neurodegenerative disease ataxia-telangiectasia. Atm-deficient (Atm-/-) mice show neurological defects detected by motor function tests including the rota-rod, open-field tests and hindpaw footprint analysis. However, no gross histological abnormalities have been observed consistently in the cerebellum of any line of Atm-/- mice analyzed in most laboratories. Therefore, it may be that the neurologic dysfunction found in these animals is associated with predegenerative lesions. We performed a detailed analysis of the cerebellar morphology in two independently generated lines of Atm-/- mice to determine whether there was evidence of neuronal abnormality. We found a significant increase in the number of lysosomes in Atm-/- mice in the absence of any detectable signs of neuronal degeneration or other ultrastructural anomalies. In addition, we found that the ATM protein is predominantly cytoplasmic in Purkinje cells and other neurons, in contrast to the nuclear localization of ATM protein observed in cultured cells. The cytoplasmic localization of ATM in Purkinje cells is similar to that found in human cerebellum. These findings suggest that ATM may be important as a cytoplasmic protein in neurons and that its absence leads to abnormalities of cytoplasmic organelles reflected as an increase in lysosomal numbers.

Background: The short-term outcomes of concussions within Major League Baseball (MLB) warrant further consideration beyond a medical standpoint given that performance, career, and financial data remain unknown. The perception of this injury directly affects decision making from the perspective of both player and franchise. Purpose: To evaluate the effect of concussion on MLB players by (1) establishing return-to-play (RTP) time after concussion; (2) comparing the career length and performance of players with concussion versus those who took nonmedical leave; and (3) analyzing player financial impact after concussion. Study Design: Cohort study; Level of evidence, 3. Methods: Contracts, transactions, injury reports, and performance statistics from 2005 to 2017 were analyzed by comparing matched players who sustained a concussion versus those who took nonmedical leave. Of the 4186 eligible MLB players, 145 sustained concussions resulting in the activation of concussion protocol and 538 took nonmedical leave. RTP time was recorded. Career length was analyzed in reference to an experience-based stratification of full seasons remaining after the concussion. Changes in player performance and salary before and after concussion were compared with the same parameters for players who took nonmedical leave. Results: The mean RTP time was 26 days (95% CI, 20-32 days) for athletes with concussion and 8 days (95% CI, 6-10 days) for those who took nonmedical leave. Athletes with concussion had a mean of 2.8 full seasons remaining, whereas athletes who took nonmedical leave had 3.1 seasons remaining (P = .493). The probability of playing in the MLB after concussion compared with the nonmedical leave pool was not significantly lower (P = .534, log-rank test; hazard ratio, 1.108). Postconcussion performance decreased significantly in position players, including a lower batting average and decreased on-base percentage in the players with concussion compared with those returning from nonmedical leave. Players who sustained a concussion lost a mean of US$654,990 annually compared with players who took nonmedical leave. Conclusion: This study of the short-term outcomes after concussion in limited-contact MLB athletes demonstrates that concussions may not decrease career spans but may result in decreased performance in addition to financial loss when compared with matched controls who took nonmedical leave. In sports such as baseball that are not subject to repetitive head trauma, career spans may not decrease after a single concussive event. However, sentinel concussions have deleterious short-term effects on performance and compensation among MLB players.

Purpose Neoadjuvant combination treatment with chemotherapy (CTX), trastuzumab (TZM), and pertuzumab (PTZ) has been shown to result in higher pathological complete response rates (pCR) in comparison with treatment with chemotherapy and trastuzumab (CTX/TZM). This analysis was aimed at real-world validation of these results from prospective randomized trials. Methods In a retrospective analysis conducted in the PRAEGNANT network, patients were eligible for inclusion if they had either received neoadjuvant therapy with CTX/TZM or chemotherapy, trastuzumab, and pertuzumab (CTX/TZM/PTZ) and subsequently underwent surgery for their primary breast cancer. The effect of the two neoadjuvant regimens on pCR in addition to commonly applicable predictors of pCR was analyzed in 300 patients from three study sites, using logistic regression analyses with treatment arm, age, clinical tumor stage, grading, and hormone receptor status as predictors. Results pCR with complete disappearance of all tumor cells was seen in 30.2% ( n  = 58) of patients treated with CTX/TZM and in 52.8% ( n  = 57) of those treated with CTX/TZM/PTZ. CTX/TZM/PTZ was positively associated with pCR (adjusted odds ratio 2.44; 95% CI 1.49–4.02). Mastectomy rates were not influenced by the therapy. Conclusions The results of clinical trials were confirmed in this dataset of patients who were treated outside of clinical trials in everyday routine work. pCR rates can be improved by 20% with pertuzumab in routine clinical use.

Background Although adequate physical activity has been shown to be beneficial in early breast cancer, evidence in metastatic breast cancer is sparse and contradictory, which could be related to distinct effects of physical activity on the different molecular cancer subtypes. Therefore, we here evaluated the effect of physical activity on progression-free and overall survival (PFS, OS) in metastatic breast cancer, specifically looking at molecular subtypes. Methods International Physical Activity Questionnaire (IPAQ) questionnaires, filled out by patients enrolled in the prospective PRAEGNANT registry (NCT02338167; n = 1,270) were used to calculate metabolic equivalent task (MET) minutes, which were subsequently categorized into low (n = 138), moderate (n = 995) or high IPAQ categories (n = 137). Cox regression analyses were used to evaluate the impact of IPAQ categories and its interaction with molecular subtypes on PFS and OS. Results Patient and tumor characteristics were equally distributed across IPAQ categories. HER2pos, HRpos and TNBC were present in 23.1%, 65.7% and 11.2% of patients, respectively. IPAQ scores did not have an impact on PFS and OS in addition to established prognostic factors, either overall or in particular molecular subtypes (PFS: p = 0.33 and OS: p = 0.08, likelihood ratio test). Exploratory analyses showed higher overall survival rates for high IPAQ categories compared to low/moderate IPAQ categories in luminal B-like breast cancer. Conclusions Self-reported physical activity using the IPAQ questionnaire did not significantly affect PFS or OS in patients suffering from metastatic breast cancer. Nevertheless, some hypothesis-generating differences between molecular subtypes could be observed, which may be interesting to evaluate further.

PurposeThe PRAEGNANT study is a registry study for metastatic breast cancer patients, focusing on biomarker detection. Recently, within this study, genetic alterations in 37 breast cancer predisposition genes were analyzed and genetic findings were detected for 396 participants. The aim of this project was to return genetic results to the physicians and to analyze actions taken (e.g., disclosure of results to patients, validation of results, clinical impact, and impact on the patient’s quality of life) using a questionnaire.Methods235 questionnaires were sent out to the study centers, with each questionnaire representing one patient with a genetic finding. The questionnaire consisted of twelve questions in the German language, referring to the disclosure of results, validation of test results, and their impact on treatment decisions and on the patient’s quality of life.Results135 (57.5%) questionnaires were completed. Of these, 46 (34.1%) stated that results were returned to the patients. In 80.0% (N = 36) of cases where results were returned, the patient had not been aware of the finding previously. For 27 patients (64.3%), genetic findings had not been validated beforehand. All validation procedures (N = 15) were covered by the patients’ health insurance. For 11 (25.0%) patients, physicians reported that the research results influenced current or future decision-making on treatment, and for 37.8% (N = 17) the results influenced whether family members will be genetically tested.ConclusionThis study provides novel insights into the return of research results and into clinical and personal benefits of disclosure of genetic findings within a German registry.