Alexander T. Augusta Military Medical Center

UNLABELLED: Chimeric antigen receptor (CAR)-modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia. Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines and clinical biomarkers in 51 CTL019-treated patients. Peak levels of 24 cytokines, including IFNγ, IL6, sgp130, and sIL6R, in the first month after infusion were highly associated with severe CRS. Using regression modeling, we could accurately predict which patients would develop severe CRS with a signature composed of three cytokines. Results were validated in an independent cohort. Changes in serum biochemical markers, including C-reactive protein and ferritin, were associated with CRS but failed to predict development of severe CRS. These comprehensive profiling data provide novel insights into CRS biology and, importantly, represent the first data that can accurately predict which patients have a high probability of becoming critically ill. SIGNIFICANCE: CRS is the most common severe toxicity seen after CAR T-cell treatment. We developed models that can accurately predict which patients are likely to develop severe CRS before they become critically ill, which improves understanding of CRS biology and may guide future cytokine-directed therapy. Cancer Discov; 6(6); 664-79. ©2016 AACR.See related commentary by Rouce and Heslop, p. 579This article is highlighted in the In This Issue feature, p. 561.

Handbook of Mental Retardation and Development, by Jacob A. Burack, Robert M. Hodapp, and Edward Zigler, Cambridge, UK, Cambridge University Press, 1998, 764 pp, $80.00 hardcover, $29.95 paperback. This book is primarily a summation and discussion of research work that will be of great interest to readers who are primarily engaged in research or who are contemplating doing research in a certain area relative to mental retardation and development. It is in no sense a textbook that attempts to pull together all of the medical, social, psychological, and educational aspects of mental retardation and development. The editors have divided the book into four parts. The first part, containing five chapters by different authors, is devoted to issues in the developmental approach to mental retardation. An introduction tracing the relationship of investigations to developmental psychology is particularly useful in offering explanations regarding the relevance of this relationship to the overall field of mental retardation. Each of the chapters has an extensive bibliography. The second part, containing eight chapters, is devoted to cognitive and linguistic development. Some of the chapters deal almost entirely with research work relating to normal development. One of the authors points out that data derived from certain studies indicate that the acquisition of sensorimotor development is more similar than different among groups of children with retardation when compared with typically developing children. The research work that supports such contentions is clearly documented throughout this section as well as in other sections. The third part, containing eight chapters, is devoted to social and emotional development. Because problems of social and emotional adjustment of children with developmental disabilities are likely to be central to functional success in society, this section will be of great interest to both researchers and clinicians. A section describing the development of friends and friendships might be interesting to people and agencies devoted to helping persons with developmental disabilities function smoothly in the community. For the most part, little research has been done on the issues surrounding the adult with developmental disabilities. The chapter by Kraus and Seltzer presents some of the work relating to life-course perspectives with special emphasis on individuals and their families. As more and more adults with developmental disabilities remain in the community, the need for research to help them achieve success in the community settings becomes increasingly needed. The fourth section, containing five chapters, is devoted to environment and family. One of the points made by Greenbaum and Auerbach is that successful adaptation to the environment on the part of the child or adult with a developmental disability depends on active and consistent intervention by the environment, which they suggest should be provided by a mentor who has continuous contact with the individual. Because this handbook is not a compendium of medical and biological information relating to developmental disabilities, it will not be of use to those who wish to find detailed information about any of the known conditions which give rise to mental retardation or developmental disabilities. On the other hand, for professional persons working in the field of mental retardation and developmental disabilities, this book will offer important insights derived from well-documented research, which will serve as a guide for understanding and dealing with the complexities surrounding the affected persons whom they are trying to serve. ROBERT B. KUGEL, M.D. DeWitt Hospital Ft. Belvoir, Virginia

Microbial agents including periodontal pathogens have recently appeared as important actors in Alzheimer's disease (AD) pathology. We examined associations of clinical periodontal and bacterial parameters with incident all-cause and AD dementia as well as AD mortality among US middle-aged and older adults. Clinical [Attachment Loss (AL); probing pocket depth (PPD)] and bacterial [pathogen immunoglobulin G (IgG)] periodontal markers were investigated in relation to AD and all-cause dementia incidence and to AD mortality, using data from the third National Health and Nutrition Examination Surveys (NHANES III, 1988-1994) linked longitudinally with National Death Index and Medicare data through January 1, 2014, with up to 26 years of follow-up. Sex- and age-specific multivariable-adjusted Cox proportional hazards models were conducted. Among those ≥65 years, AD incidence and mortality were consistently associated with PPD, two factors and one cluster comprised of IgG titers against Porphyromonas gingivalis (P. gingivalis), Prevotella melaninogenica (P. melaninogenica) and Campylobacter rectus (C. rectus) among others. Specifically, AD incidence was linked to a composite of C. rectus and P. gingivalis titers (per SD, aHR = 1.22; 95% CI, 1.04-1.43, p = 0.012), while AD mortality risk was increased with another composite (per SD, aHR = 1.46; 95% CI, 1.09-1.96, p = 0.017) loading highly on IgG for P. gingivalis, Prevotella intermedia, Prevotella nigrescens, Fusobacterium nucleatum, C. rectus, Streptococcus intermedius, Capnocylophaga Ochracea, and P. melaninogenica. This study provides evidence for an association between periodontal pathogens and AD, which was stronger for older adults. Effectiveness of periodontal pathogen treatment on reducing sequelae of neurodegeneration should be tested in randomized controlled trials.

BACKGROUND: Although myocarditis/pericarditis (MP) has been identified as an adverse event following smallpox vaccine (SPX), the prospective incidence of this reaction and new onset cardiac symptoms, including possible subclinical injury, has not been prospectively defined. PURPOSE: The study's primary objective was to determine the prospective incidence of new onset cardiac symptoms, clinical and possible subclinical MP in temporal association with immunization. METHODS: New onset cardiac symptoms, clinical MP and cardiac specific troponin T (cTnT) elevations following SPX (above individual baseline values) were measured in a multi-center prospective, active surveillance cohort study of healthy subjects receiving either smallpox vaccine or trivalent influenza vaccine (TIV). RESULTS: New onset chest pain, dyspnea, and/or palpitations occurred in 10.6% of SPX-vaccinees and 2.6% of TIV-vaccinees within 30 days of immunization (relative risk (RR) 4.0, 95% CI: 1.7-9.3). Among the 1081 SPX-vaccinees with complete follow-up, 4 Caucasian males were diagnosed with probable myocarditis and 1 female with suspected pericarditis. This indicates a post-SPX incidence rate more than 200-times higher than the pre-SPX background population surveillance rate of myocarditis/pericarditis (RR 214, 95% CI 65-558). Additionally, 31 SPX-vaccinees without specific cardiac symptoms were found to have over 2-fold increases in cTnT (>99th percentile) from baseline (pre-SPX) during the window of risk for clinical myocarditis/pericarditis and meeting a proposed case definition for possible subclinical myocarditis. This rate is 60-times higher than the incidence rate of overt clinical cases. No clinical or possible subclinical myocarditis cases were identified in the TIV-vaccinated group. CONCLUSIONS: Passive surveillance significantly underestimates the true incidence of myocarditis/pericarditis after smallpox immunization. Evidence of subclinical transient cardiac muscle injury post-vaccinia immunization is a finding that requires further study to include long-term outcomes surveillance. Active safety surveillance is needed to identify adverse events that are not well understood or previously recognized.

Syphilis is a sexually transmitted disease with varied and often subtle clinical manifestations. Primary syphilis typically presents as a solitary, painless chancre, whereas secondary syphilis can have a wide variety of symptoms, especially fever, lymphadenopathy, rash, and genital or perineal condyloma latum. In latent syphilis, all clinical manifestations subside, and infection is apparent only on serologic testing. Late or tertiary syphilis can manifest years after infection as gummatous disease, cardiovascular disease, or central nervous system involvement. Neurosyphilis can develop in any stage of syphilis. The diagnosis of syphilis may involve dark-field microscopy of skin lesions but most often requires screening with a nontreponemal test and confirmation with a treponemal-specific test. Parenterally administered penicillin G is considered first-line therapy for all stages of syphilis. Alternative regimens for nonpregnant patients with no evidence of central nervous system involvement include doxycycline, tetracycline, ceftriaxone, and azithromycin. In pregnant women and patients with neurosyphilis, penicillin remains the only effective treatment option; if these patients are allergic to penicillin, desensitization is required before treatment is initiated. Once the diagnosis of syphilis is confirmed, quantitative nontreponemal test titers should be obtained. These titers should decline fourfold within six months after treatment of primary or secondary syphilis and within 12 to 24 months after treatment of latent or late syphilis. Serial cerebrospinal fluid examinations are necessary to ensure adequate treatment of neurosyphilis.

CONTEXT: Shame and guilt are subjective emotional responses that occur in response to negative events such as the making of mistakes or an experience of mistreatment, and have been studied extensively in the field of psychology. Despite their potentially damaging effects and ubiquitous presence in everyday life, very little has been written about the impact of shame and guilt in medical education. METHODS: The authors reference the psychology literature to define shame and guilt and then focus on one area in medical education in which they manifest: the response of the learner and teacher to medical errors. Evidence is provided from the psychology literature to show associations between shame and negative coping mechanisms, decreased empathy and impaired self-forgiveness following a transgression. The authors link this evidence to existing findings in the medical literature that may be related to unrecognised shame and guilt, and propose novel ways of thinking about a learner's ability to cope, remain empathetic and forgive him or herself following an error. RESULTS: The authors combine the discussion of shame, guilt and learner error with findings from the medical education literature and outline three specific ways in which teachers might lead learners to a shame-free response to errors: by acknowledging the presence of shame and guilt in the learner; by avoiding humiliation, and by leveraging effective feedback. CONCLUSIONS: The authors conclude with recommendations for research on shame and guilt and their influence on the experience of the medical learner. This critical research plus enhanced recognition of shame and guilt will allow teachers and institutions to further cultivate the engaged, empathetic and shame-resilient learners they strive to create.

Mild, asymptomatic elevations (less than five times the upper limit of normal) of alanine transaminase and aspartate transaminase levels are common in primary care. It is estimated that approximately 10% of the U.S. population has elevated transaminase levels. An approach based on the prevalence of diseases that cause asymptomatic transaminase elevations can help clinicians efficiently identify common and serious liver disease. The most common causes of elevated transaminase levels are nonalcoholic fatty liver disease and alcoholic liver disease. Uncommon causes include drug-induced liver injury, hepatitis B and C, and hereditary hemochromatosis. Rare causes include alpha1-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease. Extrahepatic sources, such as thyroid disorders, celiac sprue, hemolysis, and muscle disorders, are also associated with mildly elevated transaminase levels. The initial evaluation should include an assessment for metabolic syndrome and insulin resistance (i.e., waist circumference, blood pressure, fasting lipid level, and fasting glucose or A1C level); a complete blood count with platelets; measurement of serum albumin, iron, total iron-binding capacity, and ferritin; and hepatitis C antibody and hepatitis B surface antigen testing. The nonalcoholic fatty liver disease fibrosis score and the alcoholic liver disease/nonalcoholic fatty liver disease index can be helpful in the evaluation of mildly elevated transaminase levels. If testing for common causes is consistent with nonalcoholic fatty liver disease and is otherwise unremarkable, a trial of lifestyle modification is appropriate. If the elevation persists, hepatic ultrasonography and further testing for uncommon causes should be considered.

PURPOSE: To develop a highly efficient magnetic field gradient coil for head imaging that achieves 200 mT/m and 500 T/m/s on each axis using a standard 1 MVA gradient driver in clinical whole-body 3.0T MR magnet. METHODS: A 42-cm inner diameter head-gradient used the available 89- to 91-cm warm bore space in a whole-body 3.0T magnet by increasing the radial separation between the primary and the shield coil windings to 18.6 cm. This required the removal of the standard whole-body gradient and radiofrequency coils. To achieve a coil efficiency ~4× that of whole-body gradients, a double-layer primary coil design with asymmetric x-y axes, and symmetric z-axis was used. The use of all-hollow conductor with direct fluid cooling of the gradient coil enabled ≥50 kW of total heat dissipation. RESULTS: diffusion, echo time (TE) < 50 ms was achieved (>50% reduction compared with whole-body gradients). The gradient coil passed the American College of Radiology tests for gradient linearity and distortion, and met acoustic requirements for nonsignificant risk operation. CONCLUSIONS: Ultra-high gradient coil performance was achieved for head imaging without substantial increases in gradient driver power in a whole-body 3.0T magnet after removing the standard gradient coil. As such, any clinical whole-body 3.0T MR system could be upgraded with 3-4× improvement in gradient performance for brain imaging.

Disorders of puberty can profoundly impact physical and psychosocial well-being. Precocious puberty is pubertal onset before eight years of age in girls and before nine years of age in boys. Patients with early isolated pubertal changes, prepubertal linear growth, and no worrisome neurologic symptoms typically have a benign pattern of development and should be monitored in the appropriate clinical context. Among patients with true precocious puberty, or full activation of the hypothalamic-pituitary-gonadal axis, most girls have an idiopathic etiology, whereas it is commonly due to identifiable pathology on imaging in boys. History and physical examination should be followed by measurements of serum follicle-stimulating hormone, luteinizing hormone, and testosterone (boys) or estradiol (girls); thyroid function testing; and bone age radiography. Brain magnetic resonance imaging should be performed in girls younger than six years, all boys with precocious puberty, and children with neurologic symptoms. Delayed puberty is the absence of breast development in girls by 13 years of age and absence of testicular growth to at least 4 mL in volume or 2.5 cm in length in boys by 14 years of age. Constitutional delay of growth and puberty is a common cause of delayed puberty; however, functional or persistent hypogonadism should be excluded. History and physical examination should be followed by measurements of serum follicle-stimulating hormone, luteinizing hormone, and testosterone (boys) or estradiol (girls); and bone age radiography. Abnormal growth velocity necessitates assessment of serum thyroid function, prolactin, and insulinlike growth factor I. Boys 14 years and older and girls 13 years and older may benefit from sex steroid treatment to jump-start puberty. Referral to a pediatric endocrinologist may be warranted after the initial evaluation.

Background: Program evaluations can serve as a doorway to research in the creative arts therapies. This study provides findings from analyses of participant feedback on short- and long- term art therapy services for military service members with post-traumatic stress and traumatic brain injury (TBI). Methods: Data for the study included feedback surveys from 204 service members who received art therapy services as part of treatment at an integrative care setting. Results: The results indicate that long-term art therapy resulted in higher satisfaction with treatment. Art therapy helped most with developing a sense of self after injury, experiencing positive emotions, processing trauma, and reducing feelings of guilt, grief, and loss. There were no statistically significant differences in outcomes based on rank or severity of TBI, but art therapy services were found to be related to improved symptoms for service members with longer times in service. Implications: The feedback from evaluation helps identify potential areas for further research on how art therapy addresses issues of identity, time in service and experiences of emotions as a result of post-traumatic stress and TBI. Evaluation provides directions for further clinical treatment, and yields data on improving quality of care.

This evidence-based review examined the evidence supporting the use of occupation-based interventions to improve areas of occupation and social participation poststroke. A total of 39 studies met the inclusion criteria and were critically evaluated. Most of the literature targeted activity of daily living (ADL)-based interventions and collectively provided strong evidence for the use of occupation-based interventions to improve ADL performance. The evidence related to instrumental ADLs was much more disparate, with limited evidence to support the use of virtual reality interventions and emerging evidence to support driver education programs to improve occupational performance poststroke. Only 6 studies addressed leisure, social participation, or rest and sleep, with sufficient evidence to support only leisure-based interventions. The implications of this review for research, education, and practice in occupational therapy are also discussed.

Management of abnormalities in water homeostasis is frequently challenging. Because age-related changes and chronic diseases are often associated with impairment of water metabolism in elderly patients, it is absolutely essential for clinicians to be aware of the pathophysiology of hyponatremia and hypernatremia in the elderly. The sensation of thirst, renal function, concentrating abilities and hormonal modulators of salt and water balance are often impaired in the elderly, which makes such patients highly susceptible to morbid and iatrogenic events involving salt and water. Clinicians should use a systematic approach in evaluating water and sodium problems, utilizing a comprehensive history and physical examination, and a few directed laboratory tests to make the clinical diagnosis. Furthermore, clinicians should have a clear appreciation of the roles that iatrogenic interventions and lapses in nutrition and nursing care frequently play in upsetting the homeostatic balance in elderly patients, particularly those who are in longterm institutional and inpatient settings.

Menstrual patterns can be an indicator of overall health and self-perception of well-being. Primary amenorrhea, defined as the lifelong absence of menses, requires evaluation if menarche has not occurred by 15 years of age or three years post-thelarche. Secondary amenorrhea is characterized by cessation of previously regular menses for three months or previously irregular menses for six months and warrants evaluation. Clinicians may consider etiologies of amenorrhea categorically as outflow tract abnormalities, primary ovarian insufficiency, hypothalamic or pituitary disorders, other endocrine gland disorders, sequelae of chronic disease, physiologic, or induced. The history should include menstrual onset and patterns, eating and exercise habits, presence of psychosocial stressors, body weight changes, medication use, galactorrhea, and chronic illness. Additional questions may target neurologic, vasomotor, hyperandrogenic, or thyroid-related symptoms. The physical examination should identify anthropometric and pubertal development trends. All patients should be offered a pregnancy test and assessment of serum follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone levels. Additional testing, including karyotyping, serum androgen evaluation, and pelvic or brain imaging, should be individualized. Patients with primary ovarian insufficiency can maintain unpredictable ovary function and may require hormone replacement therapy, contraception, or infertility services. Functional hypothalamic amenorrhea may indicate disordered eating and low bone density. Treatment should address the underlying cause. Patients with polycystic ovary syndrome should undergo screening and intervention to attenuate metabolic disease and endometrial cancer risk. Amenorrhea can be associated with clinically challenging pathology and may require lifelong treatment. Patients will benefit from ample time with the clinician, sensitivity, and emotional support.

The graduate medical education system is tasked with training competent and autonomous health care providers while also improving patient safety, delivering more efficient care, and cutting costs. Concerns about resident autonomy and preparation for independent and safe practice appear to be growing, and the field of surgery faces unique challenges in preparing graduates for independent practice. Multiple factors are contributing to an erosion of resident autonomy and decreased operative experience, including differing views of autonomy, financial forces, duty hours regulations, and diverse community health care needs. Identifying these barriers and developing solutions to overcome them are vital first steps in reversing the trend of diminishing autonomy in surgical residency training. This Commentary highlights the problem of decreasing autonomy, outlines specific threats to resident autonomy, and discusses potential solutions to mitigate their impact on the successful transition to independent practice.

Awareness of the risks of burnout, depression, learner mistreatment, and suboptimal learning environments is increasing in academic medicine. A growing wellness and resilience movement has emerged in response to these disturbing trends; however, efforts to address threats to physician resilience have often emphasized strategies to improve life outside of work, with less attention paid to the role of belonging and connection at work. In this Commentary the authors propose that connection to colleagues, patients, and profession is fundamental to medical learners' resilience, highlighting "social resilience" as a key factor in overall well-being. They outline three specific forces that drive disconnection in medical education: the impact of shift work, the impact of the electronic medical record, and the impact of "work-life balance." Finally, the authors propose ways to overcome these forces in order to build meaningful connection and enhanced resilience in a new era of medicine.

Chronic tendon injuries present unique management challenges. The assumption that these injuries result from ongoing inflammation has caused physicians to rely on treatments demonstrated to be ineffective in the long term. Nonsteroidal anti-inflammatory drugs should be limited in the treatment of these injuries. Corticosteroid injections should be considered for temporizing pain relief only for rotator cuff tendinopathy. For chronic Achilles tendinopathy (symptoms lasting longer than six weeks), an intense eccentric strengthening program of the gastrocnemius/ soleus complex improved pain and function between 60 and 90 percent in randomized trials. Evidence also supports eccentric exercise as a first-line option for chronic patellar tendon injuries. Other modalities such as prolotherapy, topical nitroglycerin, iontophoresis, phonophoresis, therapeutic ultrasound, extracorporeal shock wave therapy, and low-level laser therapy have less evidence of effectiveness but are reasonable second-line alternatives to surgery for patients who have persistent pain despite appropriate rehabilitative exercise.

The authors offer their perspective on “Hermeneutic Phenomenology” in an effort to provide clarity and direction to health professional educators

OBJECTIVE: To assess predictive value of concussion signs and symptoms based on return-to-play timelines. DESIGN: Physician practice study without diagnosis that includes presentation, initial and subsequent treatment, and management of concussion. SETTING: National multisite primary care sports medicine provider locations. PARTICIPANTS: Twenty-two providers at 18 sites; 101 athletes (91 men, 10 women in the following sports: 73 football, 8 basketball, 8 soccer, 3 wrestling, 2 lacrosse, 2 skiing, 5 others; 51 college, 44 high school, 4 professional, and 2 recreational). MAIN OUTCOME MEASUREMENTS: Duration of symptoms, presence of clinical signs, and time to return to play following concussion. RESULTS: One hundred one concussions were analyzed. Pearson chi2 analysis of common early and late concussion symptoms revealed statistical significance (P < 0.05) of headache >3 hours, difficulty concentrating >3 hours, any retrograde amnesia or loss of consciousness, and return to play >7 days. There appeared to be a trend in patients with posttraumatic amnesia toward poor outcome, but this was not statistically significant. CONCLUSIONS: When evaluating concussion, symptoms of headache >3 hours, difficulty concentrating >3 hours, retrograde amnesia, or loss of consciousness may indicate a more severe injury or prolonged recovery; great caution should be exercised before returning these athletes to play.

The purpose of this study was to examine the influence of poor effort on neuropsychological test performance in military personnel following mild traumatic brain injury (MTBI). Participants were 143 U.S. service members who sustained a TBI, divided into three groups based on injury severity and performance on the Word Memory Test and four embedded markers of poor effort: MTBI-pass (n = 87), MTBI-fail (n = 21), and STBI-pass (n = 35; where STBI denotes severe TBI). Patients were evaluated at the Walter Reed Army Medical Center on average 3.9 months (SD = 3.4) post injury. The majority of the sample was Caucasian (84.6%), was male (93.0%), and had 12+ years of education (96.5%). Measures included the Personality Assessment Inventory (PAI) and 13 common neurocognitive measures. Patients in the MTBI-fail group performed worse on the majority of neurocognitive measures, followed by the Severe TBI-Pass group and the MTBI-pass group. Using a criterion of three or more low scores <10th percentile, the MTBI-fail group had the greatest rate of impairment (76.2%), followed by the Severe TBI-Pass group (34.3%) and MTBI-pass group (16.1%). On the PAI, the MTBI-fail group had higher scores on the majority of clinical scales (p < .05). There were a greater number of elevated scales (e.g., 5 or more elevated mild or higher) in the MTBI-fail group (71.4%) than in the MTBI-pass group (32.2%) and Severe TBI-Pass group (17.1%). Effort testing is an important component of postacute neuropsychological evaluations following combat-related MTBI. Those who fail effort testing are likely to be misdiagnosed as having severe cognitive impairment, and their symptom reporting is likely to be inaccurate.

The rapid spread of the highly contagious Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) along with its high number of mutations in the spike gene has raised alarms about the effectiveness of current medical countermeasures. To address this concern, we measured the neutralization of the Omicron BA.1 variant pseudovirus by postvaccination serum samples after two and three immunizations with the Pfizer/BioNTech162b2 SARS-CoV-2 mRNA (Pfizer/BNT162b2) vaccine, convalescent serum samples from unvaccinated individuals infected by different variants, and clinical-stage therapeutic antibodies. We found that titers against the Omicron variant were low or undetectable after two immunizations and in many convalescent serum samples, regardless of the infecting variant. A booster vaccination increased titers more than 30-fold against Omicron to values comparable to those seen against the D614G variant after two immunizations. Neither age nor sex was associated with the differences in postvaccination antibody responses. We also evaluated 18 clinical-stage therapeutic antibody products and an antibody mimetic protein product obtained directly from the manufacturers. Five monoclonal antibodies, the antibody mimetic protein, three antibody cocktails, and two polyclonal antibody preparations retained measurable neutralization activity against Omicron with a varying degree of potency. Of these, only three retained potencies comparable to the D614G variant. Two therapeutic antibody cocktails in the tested panel that are authorized for emergency use in the United States did not neutralize Omicron. These findings underscore the potential benefit of mRNA vaccine boosters for protection against Omicron and the need for rapid development of antibody therapeutics that maintain potency against emerging variants.