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Journal of Women's HealthVol. 29, No. 4 CommentaryFree AccessSex and Gender Disparities in the COVID-19 PandemicJewel Gausman and Ana LangerJewel GausmanWomen & Health Initiative, Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.Search for more papers by this author and Ana LangerAddress correspondence to: Ana Langer, MD, Women & Health Initiative, Department of Global Health and Population, Harvard T.H. Chan School of Public Health, 651 Huntington Avenue, FXB Building 6th Floor Office 643B, Boston, MA 02115 E-mail Address: [email protected]Women & Health Initiative, Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.Search for more papers by this authorPublished Online:17 Apr 2020https://doi.org/10.1089/jwh.2020.8472AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookXLinked InRedditEmail In the case of the ongoing COVID-19 pandemic, sex-disaggregated data suggest that fewer women are dying from the disease than men.1 However, taking this observation at face value oversimplifies the biological, behavioral, and social and systemic factors that may cause differences to emerge with regard to how women and men experience both the disease and its consequences. As governments react with swift and severe measures in their ongoing fight to control the pandemic's spread, it is important to understand how these actions may disproportionately increase the risks for women both directly and indirectly with regard to sex and gender.Pregnant women are often among the most vulnerable groups during public health emergencies. In some cases, pregnant women face increased biological susceptibility to adverse health outcomes, as in the case of some respiratory infections. With other emergent coronaviruses, such as those responsible for severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS), pregnant women who became infected were found to be more likely than nonpregnant women to experience severe complications.2 It is still too early to tell whether this will be the case with COVID-19.In the ongoing pandemic, other factors may have a ripple effect that put women at increased risk even if the disease itself does not. As made clear during the 2014 Ebola outbreak, the consequences of large-scale infectious disease outbreaks on uninfected pregnant women can be dire. Routine prenatal care appointments, if not interrupted or discontinued, may put women at increased risk of exposure to the virus. Overwhelmed hospitals struggling to function with staff and supply shortages may not be able to provide the high quality of care that all pregnant women and their newborns deserve, let alone respond to emergency obstetric complications. Furthermore, there is also a risk that life-saving treatments or vaccines will be denied to pregnant women over concern for fetal safety or a lack of data.3,4The fear of infection, concern for the well-being of friends and loved ones, uncertainty, disruption, and social isolation that have become part and parcel of daily life for many around the world will undoubtedly have profound effects on mental health on the population at large, but being pregnant during a global pandemic is likely to be even more frightening for many women. Although containment strategies, such as those that require women to deliver without a companion present, including partners and doulas, that have already been put into place in some cities in the United States,5 or those that separate newborns from their mothers immediately after birth if the mother is infected with COVID-196 may be clinically important to reduce transmission, they may also have profound short- and long-term mental health implications for women. Among women who have young children, previous research in Ethiopia, India, and Vietnam found that women who experience family-related stressful life events, such as illness or death within the household and financial uncertainty, are more likely to experience episodes of severe mental distress.7 With the ongoing need to social distance, family and community networks may struggle and pregnant and postpartum women may feel even more vulnerable and isolated over a lack of social support.The adverse effects of the pandemic in relation to women's reproductive health are not limited to pregnancy or motherhood. As movement restrictions are put into place, supply chains are disrupted, and businesses are shuttered, some women may be at increased risk of unintended pregnancy should it become difficult to obtain their regular contraceptive method or emergency contraceptives, if needed. Furthermore, some states within the United States have begun to impose restrictions on certain medical procedures that they deem to be elective, including abortion, suggesting they must be delayed until after the pandemic is over.8 Spikes in domestic violence during times of crisis are another area of grave concern for women's health, and as governments continue to put into place more extreme measures to enforce social distancing, for some women, more time at home may mean more time spent with an abusive partner. Fewer social interactions may also mean less accountability for perpetrators and fewer opportunities for others to intervene.Gender-related factors may also increase the impact of the COVID-19 pandemic on women globally. Women constitute a disproportionately high percentage of caregivers in both the formal and informal sectors.9 A large proportion of frontline health care professionals (nurses, community health workers, health technicians, etc.) is women who face a higher risk of infection, morbidity, and death as a result of their profession.9 At the same time, women more frequently serve as the primary caregivers within a household, which may further increase their risk of exposure. In the United States, 65% of unpaid family caregivers are estimated to be women and 80% of them care for someone aged 50 years or older.10 Outside of their caregiving role, women are overrepresented in the informal employment sector. In low-and middle-income countries, two-thirds of women who work do so as part of the informal economy with limited access to health care for themselves and their families.9 Containment and mitigation policies that limit women's ability to perform their duties without offering effective alternatives, such as closing of daycare facilities for their children or not providing paid sick leave, may result in unnecessary exposure to disease and increased family vulnerability.It is urgent that we adopt a gender lens to study the pandemic and its effects, including the policies and actions that are put into place at the global, country, and local levels. This may be especially important in disadvantaged populations and resource-poor communities, where women are especially vulnerable. The public health community must ensure that existing health and social services meant to support women in the face of their unique needs do not disappear in lieu of the all-encompassing focus on stopping the pandemic. Furthermore, we argue that special attention needs to be paid to ensure that informal caregivers are supported, informed, and protected. To avoid making existing gender disparities larger as a result of the pandemic, a special body at the U.S. Centers of Disease Control and Prevention is urgently needed to track sex disaggregated data and analyze policies related to COVID-19 using a gender lens.Author Disclosure StatementNo competing financial interests exist.Funding InformationNo funding was received for this article.References1. Cai H. Sex difference and smoking predisposition in patients with COVID-19. Lancet Respir Med 2020;pii: S2213-2600(20)30117-X. Medline, Google Scholar2. Favre G, Pomar L, Musso D, Baud D. 2019-nCoV epidemic: What about pregnancies? Lancet 2020;395:e40. Crossref, Medline, Google Scholar3. Rasmussen SA, Smulian JC, Lednicky JA, Wen TS, Jamieson DJ. Coronavirus disease 2019 (COVID-19) and pregnancy: What obstetricians need to know. Am J Obstet Gynecol 2020;pii: S0002-9378(20)30197-6. Medline, Google Scholar4. Weigel G. Novel coronavirus "COVID-19": Special considerations for pregnant women. Available at: https://www.kff.org/womens-health-policy/issue-brief/novel-coronavirus-covid-19-special-considerations-for-pregnant-women/?utm_source=Global+Health+NOW+Main+List Accessed March 17, 2020. Google Scholar5. Caron C, Syckle KV. Laboring alone: Some hospitals bar partners because of virus fears. The New York Times. 2020. Google Scholar6. American College of Obstetricians and Gynecologists. Practice advisory: Novel coronavirus 2019 (COVID-19). Available at: https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Advisories/Practice-Advisory-Novel-Coronavirus2019?IsMobileSet=false Accessed March 13, 2020. Google Scholar7. Gausman J, Austin SB, Subramanian S, Langer A. Adversity, social capital, and mental distress among mothers of small children: A cross-sectional study in three low and middle-income countries. PLoS One 2020;15:e0228435. Crossref, Medline, Google Scholar8. Tavernise S. Texas and Ohio include abortion as medical procedures that must be delayed. The New York Times. 2020. Google Scholar9. Langer A, Meleis A, Knaul FM, et al. Women and health: The key for sustainable development. Lancet 2015;386:1165–1210. Crossref, Medline, Google Scholar10. Feinberg L, Reinhard SC, Houser A, Choula R. Valuing the invaluable: 2011 update, the growing contributions and costs of family caregiving. Washington, DC: AARP Public Policy Institute, 2011:32. 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BACKGROUND: Those immunocompromised by AIDS or cancer chemotherapy use marijuana to allay symptoms of their disease or treatment. Some researchers believe that marijuana may further suppress the immune system. A list of immunological hazards that may be present in marijuana was collated and assessed, and clinical recommendations regarding the use of marijuana by immunocompromised individuals were made. METHODS: Databases and other sources from 1964 to 1996 were searched using keywords (e.g., cannabinoids, cannabis, hemp, marijuana). This was supplemented by a manual search of bibliographies, nonindexed books, and journals, and by consultation with experts. All reports were analyzed for antecedent sources. Data validity was assessed by source, identification methodology, and frequency of independent observations. RESULTS: Substances implicated as potential immunological hazards in marijuana include endogenous constituents (cannabinoids, pyrolyzed gases, and particulates) and a longer list of exogenous contaminants, both natural (fungi and their metabolites) and synthetic (pesticides and adulterants). CONCLUSION: Burning of marijuana creates toxins of combustion. Particulate toxins (tars) are reduced by the use of vaporizer apparati. Gas-phase toxins are filtered by water pipes, but water pipes also filter some tetrahydrocannabinol, making this strategy counterproductive. Viable fungal spores in marijuana pose the greatest hazard to immunocompromised patients, though they can be sterilized by several methods. Pesticide residues and other adulterants may be present in black-market marijuana, but are absent in sources of marijuana that are approved by the Food and Drug Administration.

OBJECTIVE: To advocate formal subclassification of autoimmune hepatitis into two types based on the presence of mutually exclusive immunoserological markers, target antigen diversity, contrasting genetic predispositions, and differences in clinical profile and behavior. METHODS: Relevant references in English were identified through a Medline Search (1984-1994) and through a personal library of journals and reprints. RESULTS: Antinuclear antibodies and/or smooth-muscle antibodies are mutually exclusive of antibodies to liver/kidney microsome type 1. The cytochrome monooxygenase P450 IID6 is the target autoantigen for patients with antibodies to liver/kidney microsome type 1, and patients with these autoantibodies are different from others. The human lymphocyte antigens DR3 and DR4 are risk factors for patients with antinuclear and/or smooth-muscle antibodies, whereas the B14, DR3, and C4A-QO antigens are common in patients with antibodies to liver/kidney microsome type 1. Patients with antibodies to liver/kidney type 1 are younger, and they more commonly have concurrent organ-specific autoantibodies and/or immunological diseases than counterparts with antinuclear and/or smooth-muscle antibodies. They also progress to cirrhosis more frequently. CONCLUSIONS: Two distinct types of autoimmune hepatitis can be defined by immunoserological markers, genetic predispositions, autoantigen status, and clinical features. Each should be recognized as a valid and independent entity.

Objective: Psychosocial associations have been observed with level of cervical dysplasia or “pre-cancer” and invasive cervical cancer [related to human papillomavirus (HPV) infection]. Psychoneuroimmunological relationships have been observed in human immunodeficiency virus type 1 (HIV-1) infection, which is being described in an increasing number of women. Our objective was to review these relationships regarding effects that might be expected in HIV-1 and HPV co-infected women. Method: This review was based on a Medline literature search supplemented by a manual search of selected journals unrepresented in that database. Results: Relationships of psychosocial factors and level of cervical dysplasia were similarly observed with reference to immunological and health status in asymptomatic and early symptomatic HIV-1 infected homosexual men, suggesting that a potentiating effect may occur in HIV-1 and HPV co-infected women. Consistency of relationships across studies appeared to be enhanced by the use of a biopsychosocial model integrating the effects of life stressors, social support and coping style as well as psychiatric disorders. Conclusions: Research is indicated on the relationships between psychosocial factors, immunological status and clinical health status in this group of women. Because of the high prevalence of psychosocial risk factors for chronic psychological distress in these women and the known immunological and health status decrements occurring with progression of these two infections, a clinical screening program based on the biopsychosocial model is recommended as a means of secondary prevention. If effective in generating treatment referrals, such a program would likely improve quality of life and could aid in the determination of relationships with immunological and health status as well.

BACKGROUND: Having cancer may result in extensive emotional, physical and social suffering. Music interventions have been used to alleviate symptoms and treatment side effects in cancer patients. OBJECTIVES: To assess and compare the effects of music therapy and music medicine interventions for psychological and physical outcomes in people with cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, Science Citation Index, CancerLit, CAIRSS, Proquest Digital Dissertations, ClinicalTrials.gov, Current Controlled Trials, the RILM Abstracts of Music Literature, http://www.wfmt.info/Musictherapyworld/ and the National Research Register. We searched all databases, except for the last two, from their inception to January 2016; the other two are no longer functional, so we searched them until their termination date. We handsearched music therapy journals, reviewed reference lists and contacted experts. There was no language restriction. SELECTION CRITERIA: We included all randomized and quasi-randomized controlled trials of music interventions for improving psychological and physical outcomes in adult and pediatric patients with cancer. We excluded participants undergoing biopsy and aspiration for diagnostic purposes. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data and assessed the risk of bias. Where possible, we presented results in meta-analyses using mean differences and standardized mean differences. We used post-test scores. In cases of significant baseline difference, we used change scores. MAIN RESULTS: We identified 22 new trials for inclusion in this update. In total, the evidence of this review rests on 52 trials with a total of 3731 participants. We included music therapy interventions offered by trained music therapists, as well as music medicine interventions, which are defined as listening to pre-recorded music, offered by medical staff. We categorized 23 trials as music therapy trials and 29 as music medicine trials.The results suggest that music interventions may have a beneficial effect on anxiety in people with cancer, with a reported average anxiety reduction of 8.54 units (95% confidence interval (CI) -12.04 to -5.05, P < 0.0001) on the Spielberger State Anxiety Inventory - State Anxiety (STAI-S) scale (range 20 to 80) and -0.71 standardized units (13 studies, 1028 participants; 95% CI -0.98 to -0.43, P < 0.00001; low quality evidence) on other anxiety scales, a moderate to strong effect. Results also suggested a moderately strong, positive impact on depression (7 studies, 723 participants; standardized mean difference (SMD): -0.40, 95% CI -0.74 to -0.06, P = 0.02; very low quality evidence), but because of the very low quality of the evidence for this outcome, this result needs to be interpreted with caution. We found no support for an effect of music interventions on mood or distress.Music interventions may lead to small reductions in heart rate, respiratory rate and blood pressure but do not appear to impact oxygen saturation level. We found a large pain-reducing effect (7 studies, 528 participants; SMD: -0.91, 95% CI -1.46 to -0.36, P = 0.001, low quality evidence). In addition, music interventions had a small to moderate treatment effect on fatigue (6 studies, 253 participants; SMD: -0.38, 95% CI -0.72 to -0.04, P = 0.03; low quality evidence), but we did not find strong evidence for improvement in physical functioning.The results suggest a large effect of music interventions on patients' quality of life (QoL), but the results were highly inconsistent across studies, and the pooled effect size for the music medicine and music therapy studies was accompanied by a large confidence interval (SMD: 0.98, 95% CI -0.36 to 2.33, P = 0.15, low quality evidence). A comparison between music therapy and music medicine interventions suggests a moderate effect of music therapy interventions for patients' quality of life (QoL) (3 studies, 132 participants; SMD: 0.42, 95% CI 0.06 to 0.78, P = 0.02; very low quality evidence), but we found no evidence of an effect for music medicine interventions. A comparison between music therapy and music medicine studies was also possible for anxiety, depression and mood, but we found no difference between the two types of interventions for these outcomes.The results of single studies suggest that music listening may reduce the need for anesthetics and analgesics as well as decrease recovery time and duration of hospitalization, but more research is needed for these outcomes.We could not draw any conclusions regarding the effect of music interventions on immunologic functioning, coping, resilience or communication outcomes because either we could not pool the results of the studies that included these outcomes or we could only identify one trial. For spiritual well-being, we found no evidence of an effect in adolescents or young adults, and we could not draw any conclusions in adults.The majority of studies included in this review update presented a high risk of bias, and therefore the quality of evidence is low. AUTHORS' CONCLUSIONS: This systematic review indicates that music interventions may have beneficial effects on anxiety, pain, fatigue and QoL in people with cancer. Furthermore, music may have a small effect on heart rate, respiratory rate and blood pressure. Most trials were at high risk of bias and, therefore, these results need to be interpreted with caution.

BACKGROUND: Extracellular vesicles (EVs) play an essential role in the communication between cells and transport of diagnostically significant molecules. A wide diversity of approaches utilizing different biochemical properties of EVs and a lack of accepted protocols make data interpretation very challenging. SCOPE OF REVIEW: This review consolidates the data on the classical and state-of-the-art methods for isolation of EVs, including exosomes, highlighting the advantages and disadvantages of each method. Various characteristics of individual methods, including isolation efficiency, EV yield, properties of isolated EVs, and labor consumption are compared. MAJOR CONCLUSIONS: A mixed population of vesicles is obtained in most studies of EVs for all used isolation methods. The properties of an analyzed sample should be taken into account when planning an experiment aimed at studying and using these vesicles. The problem of adequate EVs isolation methods still remains; it might not be possible to develop a universal EV isolation method but the available protocols can be used towards solving particular types of problems. GENERAL SIGNIFICANCE: With the wide use of EVs for diagnosis and therapy of various diseases the evaluation of existing methods for EV isolation is one of the key problems in modern biology and medicine.

Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and many patients are diagnosed with advanced disease. The treatment of advanced liver cancer has made significant strides in recent years, owing to the practice of immunotherapy drugs. Numerous studies have been published on immunotherapy for HCC; however, no relevant bibliometric study has been published. This study aims to gain a better understanding of the current situation and to identify potential new research directions by conducting a bibliometric analysis on immunotherapy for HCC. Methods We searched the Web of Science Core Collection (WoSCC) for articles related to immunotherapy for HCC. Three software (VOSviewer, CiteSpace, and python) were primarily used to assess the contribution and co-occurrence relationships of various countries/regions, institutes, journals, and, authors as well as to identify research hotspots and promising future trends in this research field. Results A total of 1,641 English articles published between 2011 and 2020 were collected, with the number of articles increasing nearly every year. The majority of publications originated from China ( n = 893, 54.42%), followed by the United States and Japan. The Sun Yat-sen University contributed the most publications ( n = 97, 5.91%). Nakatsura Tetsuya ( n = 26) and Llovet JM ( n = 366) were ranked first in the top ten authors and co-cited authors. Cancer Immunology Immunotherapy was the most productive academic journal on immunotherapy for HCC [ n = 46, 2.80%; impact factor (IF) 2020 = 6.9679]. Aggregation and identification of critical nodes in the co-cited network demonstrated a shift in the field of HCC immunotherapy. Initially, the hotspots were predominantly “glypican-3”, “cytokine-induced killer cells”, and “ny-eso-1”, while the emphasis has shifted in recent years to “landscape”, “camrelizumab”, “combination therapy”, and “immune score”. Conclusion Increased attention has been paid to HCC with the advancement of immunotherapy. At the moment, the most active frontiers are focused on better understanding the immunological landscape of liver cancer, screening the population that can benefit from immunotherapy, and the clinical application of immune checkpoint inhibitors, particularly in combination with other therapeutic options (such as local therapy and targeted therapy).

BACKGROUND: Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. METHODS: We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. RESULTS: A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006). CONCLUSIONS: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).

OBJECTIVE: The aim of this review is to elucidate the biochemical, molecular, immunological, and pharmaceutical mechanisms of action of ozone dissolved in biological fluids. Studies performed during the last two decades allow the drawing of a comprehensive framework for understanding and recommending the integration of ozone therapy for spinal pain. METHODS: An in-depth screening of primary sources of information online - via SciFinder Scholar, Google Scholar, and Scopus databases as well as Embase, PubMed, and the Cochrane Database of Systemic Reviews - was performed. In this review, the most significant papers of the last 25 years are presented and their proposals critically evaluated, regardless of the bibliometric impact of the journals. RESULTS: The efficacy of standard treatments combined with the unique capacity of ozone therapy to reactivate the innate antioxidant system is the key to correcting the oxidative stress typical of chronic inflammatory diseases. Pain pathways and control systems of algesic signals after ozone administration are described. CONCLUSION: This paper finds favors the full insertion of ozone therapy into pharmaceutical sciences, rather than as either an alternative or an esoteric approach.

One of the most important branches of genetic engineering is the expression of recombinant proteins using biological expression systems. Nowadays, different expression systems are used for the production of recombinant proteins including bacteria, yeasts, molds, mammals, plants, and insects. Yeast expression systems such as Saccharomyces cerevisiae (S. cerevisiae) and Pichia pastoris (P. pastoris) are more popular. P. pastoris expression system is one of the most popular and standard tools for the production of recombinant protein in molecular biology. Overall, the benefits of protein production by P. pastoris system include appropriate folding (in the endoplasmic reticulum) and secretion (by Kex2 as signal peptidase) of recombinant proteins to the external environment of the cell. Moreover, in the P. pastoris expression system due to its limited production of endogenous secretory proteins, the purification of recombinant protein is easy. It is also considered a unique host for the expression of subunit vaccines which could significantly affect the growing market of medical biotechnology. Although P. pastoris expression systems are impressive and easy to use with well-defined process protocols, some degree of process optimization is required to achieve maximum production of the target proteins. Methanol and sorbitol concentration, Mut forms, temperature and incubation time have to be adjusted to obtain optimal conditions, which might vary among different strains and externally expressed protein. Eventually, optimal conditions for the production of a recombinant protein in P. pastoris expression system differ according to the target protein.

Purpose: To examine the cost-effectiveness of empirical, parenteral antibiotic treatment of patients with chronic fatigue and myalgia and a positive serologic result for Lyme disease who lack classic manifestations. Data Sources: Peer-reviewed journals, opinion of experts in the field, and published epidemiologic reports. Study Selection: Consensus by authors on articles that indicated methods for patient selection; on criteria used for diagnosis; on immunologic methods used for classifying patients; on the dose and duration of therapy; and on criteria by which responses to therapy were ascertained. Data Extraction: In a cost-effectiveness model, the costs and benefits of empirical parenteral therapy for patients seropositive for Lyme disease were compared with a strategy in which only patients having classical symptoms of Lyme disease were treated. Data Synthesis: In areas endemic for Lyme disease, the incidence of false-positive serologic results in patients with nonspecific myalgia or fatigue exceeds by four to one the incidence of true-positive results in patients with nonclassical infections. Treatment of the former group of patients costs $86 221 for each true-positive patient treated. The empirical strategy causes 29 cases of drug toxicity for every case in the more conservative strategy. If patients were willing to pay $3485 to eliminate anxiety about not treating possible true Lyme disease, the empirical strategy would break even. Conclusion: For most patients with a positive Lyme antibody titer whose only symptoms are nonspecific myalgia or fatigue the risks and costs of empirical parenteral antibiotic therapy exceed the benefits. Only when the value of patient anxiety about leaving a positive test untreated exceeds the cost of such therapy is the empirical treatment cost-effective.