S.P.E.C.I.E.S.

BACKGROUND: A worldwide outbreak of severe acute respiratory syndrome (SARS) has been associated with exposures originating from a single ill health care worker from Guangdong Province, China. We conducted studies to identify the etiologic agent of this outbreak. METHODS: We received clinical specimens from patients in seven countries and tested them, using virus-isolation techniques, electron-microscopical and histologic studies, and molecular and serologic assays, in an attempt to identify a wide range of potential pathogens. RESULTS: None of the previously described respiratory pathogens were consistently identified. However, a novel coronavirus was isolated from patients who met the case definition of SARS. Cytopathological features were noted in Vero E6 cells inoculated with a throat-swab specimen. Electron-microscopical examination revealed ultrastructural features characteristic of coronaviruses. Immunohistochemical and immunofluorescence staining revealed reactivity with group I coronavirus polyclonal antibodies. Consensus coronavirus primers designed to amplify a fragment of the polymerase gene by reverse transcription-polymerase chain reaction (RT-PCR) were used to obtain a sequence that clearly identified the isolate as a unique coronavirus only distantly related to previously sequenced coronaviruses. With specific diagnostic RT-PCR primers we identified several identical nucleotide sequences in 12 patients from several locations, a finding consistent with a point-source outbreak. Indirect fluorescence antibody tests and enzyme-linked immunosorbent assays made with the new isolate have been used to demonstrate a virus-specific serologic response. This virus may never before have circulated in the U.S. population. CONCLUSIONS: A novel coronavirus is associated with this outbreak, and the evidence indicates that this virus has an etiologic role in SARS. Because of the death of Dr. Carlo Urbani, we propose that our first isolate be named the Urbani strain of SARS-associated coronavirus.

BACKGROUND: It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited. METHODS: (cholecalciferol) at a dose of 2000 IU per day and marine n-3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo. RESULTS: A total of 25,871 participants, including 5106 black participants, underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified. CONCLUSIONS: Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .).

OBJECTIVE: Two studies using cross-sectional designs explored four possible mechanisms by which loneliness may have deleterious effects on health: health behaviors, cardiovascular activation, cortisol levels, and sleep. METHODS: In Study 1, we assessed autonomic activity, salivary cortisol levels, sleep quality, and health behaviors in 89 undergraduate students selected based on pretests to be among the top or bottom quintile in feelings of loneliness. In Study 2, we assessed blood pressure, heart rate, salivary cortisol levels, sleep quality, and health behaviors in 25 older adults whose loneliness was assessed at the time of testing at their residence. RESULTS: Total peripheral resistance was higher in lonely than nonlonely participants, whereas cardiac contractility, heart rate, and cardiac output were higher in nonlonely than lonely participants. Lonely individuals also reported poorer sleep than nonlonely individuals. Study 2 indicated greater age-related increases in blood pressure and poorer sleep quality in lonely than nonlonely older adults. Mean salivary cortisol levels and health behaviors did not differ between groups in either study. CONCLUSIONS: Results point to two potentially orthogonal predisease mechanisms that warrant special attention: cardiovascular activation and sleep dysfunction. Health behavior and cortisol regulation, however, may require more sensitive measures and large sample sizes to discern their roles in loneliness and health.

BACKGROUND: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible. RESULTS: A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed. CONCLUSIONS: Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163.).

BACKGROUND: Low birth weight has been associated with several chronic diseases in adults, including hypertension, diabetes mellitus, and obesity. Further study of these diseases in a large cohort with information on a wide variety of risk factors is essential to determine more precisely the risks associated with birth weight. METHODS AND RESULTS: We examined the relation between birth weight and cumulative incidence of adult hypertension, incidence of non-insulin-dependent diabetes mellitus, and prevalence of obesity in a cohort of 22,846 US men (Health Professionals Follow-up Study). Birth weights, medical histories, family histories, and other factors were collected by biennial mailed questionnaires. Logistic regression was used to examine the association between birth weight and these chronic adult diseases. Low birth weight was associated with an increased risk of hypertension and diabetes; high birth weight was associated with an increased risk of obesity. Compared with men in the referent birth weight category (7.0 to 8.4 lb), men who weighed < 5.5 lb had an age-adjusted odds ratio for hypertension of 1.26 (95% confidence interval [CI], 1.11 to 1.44) and for diabetes mellitus of 1.75 (95% CI, 1.21 to 2.54). There was no material change after controlling for adult body mass index and parental histories of hypertension and diabetes mellitus. Compared with men in the referent group, the age-adjusted odds ratio of being in the highest versus the lowest quintile of adult body mass index for men with birth weight > or = 10.0 lb was 2.08 (95% CI, 1.73 to 2.50). CONCLUSIONS: These findings support the hypothesis that early life exposures, for which birth weight is a marker, are associated with several chronic diseases in adulthood.

UNLABELLED: The current risk of infection in contemporary total knee arthroplasty (TKA) as well as the relative importance of risk factors remains under debate as a result of the rarity of the complication and temporal changes in the treatment and prevention of infection. We therefore determined infection incidence and risk factors after TKA in the Medicare population. The Medicare 5% national sample administrative data set was used to identify and longitudinally follow patients undergoing TKA for deep infections and revision surgery between 1997 and 2006. Cox regression was used to evaluate patient and hospital characteristics. In 69,663 patients undergoing elective TKA, 1400 TKA infections were identified. Infection incidence within 2 years was 1.55%. The incidence between 2 and up to 10 years was 0.46%. Women had a lower risk of infection than men. Comorbidities also increased TKA infection risk. Patients receiving public assistance for Medicare premiums were at increased risk for periprosthetic joint infection (PJI). Hospital factors did not predict an increased risk of infection. PJI occurs at a relatively high rate in Medicare patients with the greatest risk of PJI within the first 2 years after surgery; however, approximately one-fourth of all PJIs occur after 2 years. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

BACKGROUND: Low birth weight has been associated with an increased risk of hypertension, and high birth weight has been associated with increased adult body mass index. Published studies on adults have included only a small number of women. METHODS AND RESULTS: We studied 71 100 women in the Nurses Health Study I (NHS I) who were 30 to 55 years of age in 1976 and 92 940 women in the Nurses' Health Study II (NHS II) who were 25 to 42 years of age in 1989. Information on birth weight, blood pressure, physician-diagnosed hypertension, and other relevant variables was collected by biennial mailed questionnaire. Ninety-five percent of the women were white. Compared with women in the middle category of birth weight (NHS I, 7.1 to 8.5 lb; NHS II, 7.0 to 8.4 lb), the age-adjusted odds ratio of hypertension in NHS I women with birth weights < 5.0 lb was 1.39 (95% CI, 1.29 to 1.50); in NHS II, for birth weights < 5.5 lb, the age-adjusted odds ratio was 1.43 (95% CI, 1.31 to 1.56). There was no material change in the estimates after adjustment for other risk factors. In addition, compared with women in NHS I who weighed 7.1 to 8.5 lb at birth, those who weighed > 10 lb had an age-adjusted odds ratio of 1.62 (95% CI, 1.38 to 1.90) of being in the highest (> 29.2 kg/m2) versus the lowest (< 21.9 kg/ m2) quintile of body mass index in midlife. Similar results were seen in the NHS II cohort. CONCLUSIONS: Early life exposures affecting birth weight may be important in the development of hypertension and obesity in adults.

BACKGROUND: Health literacy is the single best predictor of an individual's health status. It is important to customize health-related education material to the individual patient's level of reading skills. Readability of a given text is the objective measurement of the reading skills one should possess to understand the written material. QUESTIONS/PURPOSES: In this article, some of the commonly used readability assessment tools are discussed and guidelines to improve the comprehension of patient education handouts are provided. Where are we now? Several healthcare organizations have recommended the readability of patient education materials be no higher than sixth- to eighth-grade level. However, most of the patient education materials currently available on major orthopaedic Web sites are written at a reading level that may be too advanced for comprehension by a substantial proportion of the population. WHERE DO WE NEED TO GO?: There are several readily available and validated tools for assessing the readability of written materials. While use of audiovisual aids such as video clips, line drawings, models, and charts can enhance the comprehension of a health-related topic, standard readability tools cannot construe such enhancements. HOW DO WE GET THERE?: Given the variability in the capacity to comprehend health-related materials among individuals seeking orthopaedic care, stratifying the contents of patient education materials at different levels of complexity will likely improve health literacy and enhance patient-centered communication.

BACKGROUND: Few studies have examined factors that affect acetabular cup positioning. Since cup positioning has been linked to dislocation and increased bearing surface wear, these factors affecting cup position are important considerations. QUESTION/PURPOSES: We determined the percent of optimally positioned acetabular cups and whether patient and surgical factors affected acetabular component position. METHODS: We obtained postoperative AP pelvis and cross-table lateral radiographs on 2061 consecutive patients who received a THA or hip resurfacing from 2004 to 2008. One thousand nine hundred and fifty-two hips had AP pelvic radiographs with correct position of the hip center, and 1823 had both version and abduction angles measured. The AP radiograph was measured using Hip Analysis Suite™ to calculate the cup inclination and version angles, using the lateral film to determine version direction. Acceptable ranges were defined for abduction (30°-45°) and version (5°-25°). RESULTS: From the 1823 hips, 1144 (63%) acetabular cups were within the abduction range, 1441 (79%) were within the version range, and 917 (50%) were within the range for both. Surgical approach, surgeon volume, and obesity (body mass index > 30) independently predicted malpositioned cups. Comparison of low versus high volume surgeons, minimally invasive surgical versus posterolateral approach, and obesity versus all other body mass index groups showed a twofold (1.5-2.8), sixfold (3.5-10.7), and 1.3-fold (1.1-1.7) increased risk for malpositioned cups, respectively. CONCLUSIONS: Factors correlated to malpositioned cups included surgical approach, surgeon volume, and body mass index with increased risk of malpositioning for minimally invasive surgical approach, low volume surgeons, and obese patients. Further analyses on patient and surgical factors' influence on cup position at a lower volume medical center would provide a valuable comparison. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

ABSTRACT: The COVID-19 pandemic has disrupted teaching in a variety of institutions, especially in medical schools. Electronic learning (e-learning) became the core method of teaching the curriculum during the pandemic. After 8 weeks of only online learning, a survey was conducted to investigate perception of this type of learning among medical students.A survey was conducted by distributing an online questionnaire to Polish medical students. Data gathered from the survey were analyzed with routine statistical software.Eight hundred four students answered the questionnaire. According to respondents' answers, the main advantages of online learning were the ability to stay at home (69%), continuous access to online materials (69%), learning at your own pace (64%), and comfortable surroundings (54%). The majority of respondents chose lack of interactions with patients (70%) and technical problems with IT equipment (54%) as the main disadvantages. There was no statistical difference between face-to-face and online learning in terms of opinions on the ability of the learning method to increase knowledge (P = .46). E-learning was considered less effective than face-to-face learning in terms of increasing skills (P < .001) and social competences (P < .001). Students assessed that they were less active during online classes compared to traditional classes (P < .001). E-learning was rated as enjoyable by 73% of respondents.E-learning is a powerful tool for teaching medical students. However, successful implementation of online learning into the curriculum requires a well thought-out strategy and a more active approach.

Although clinical observations suggest that alexithymic individuals have a deficit in their ability to recognize emotional stimuli and that this deficit is not simply due to a problem in verbal labeling, these two hypotheses have not been empirically confirmed. Three hundred eighty participants in a community survey without current or past histories of psychiatric disorder completed two independent measures of alexithymia [the Levels of Emotional Awareness Scale (LEAS) and the Toronto Alexithymia Scale (TAS-20)] and the Perception of Affect Task (PAT), a 140-item measure of the ability to match emotion stimuli. The PAT includes four subtasks that require the subject to match verbal or nonverbal emotion stimuli with verbal or nonverbal emotion responses. The subtasks include matching sentences and words (verbal-verbal), faces and words (nonverbal-verbal), sentences and faces (verbal-nonverbal), and faces and photographs of scenes (nonverbal-nonverbal). Across the entire sample, higher (alexithymic) TAS-20 and lower LEAS scores were both correlated with lower accuracy rates on each of the subtasks of the PAT (p < .001), accounting for 10.5% and 18.4% of the variance, respectively. Fifty-one subjects met TAS-20 criteria for alexithymia. Alexithymic individuals scored lower than other subjects on purely nonverbal matching, purely verbal matching, and mixed verbal-nonverbal matching (all p < .001). These results suggest that alexithymia is associated with impaired verbal and nonverbal recognition of emotion stimuli and that the hallmark of alexithymia, a difficulty in putting emotion into words, may be a marker of a more general impairment in the capacity for emotion information processing.

BACKGROUND: The purpose of this study was to examine prospectively the relation of shift work to risk of coronary heart disease (CHD) in a cohort of women. METHODS AND RESULTS: An ongoing prospective cohort of US female nurses, in whom we assessed (in 1988) the total number of years during which they worked rotating night shifts (at least three nights per month in addition to day and evening shifts), included 79,109 women, 42 to 67 years old in 1988, who were free of diagnosed CHD and stroke. Incident CHD was defined as nonfatal myocardial infarction and fatal CHD. During 4 years of follow-up (1988 to 1992), 292 cases of incident CHD (248 nonfatal myocardial infarction and 44 fatal CHD) occurred. The age-adjusted relative risk of CHD was 1.38 (95% CI, 1.08 to 1.76) in women who reported ever doing shift work compared with those who had never done so. The excess risk persisted after adjustment for cigarette smoking and a variety of other cardiovascular risk factors. Compared with women who had never done shift work, the multivariate adjusted relative risks of CHD were 1.21 (95% CI, 0.92 to 1.59) among women reporting less than 6 years and 1.51 (95% CI, 1.12 to 2.03) among those reporting 6 or more years of rotating night shifts. CONCLUSIONS: These data are compatible with the possibility that 6 or more years of shift work may increase the risk of CHD in women.

UNLABELLED: Total ankle arthroplasty provides an alternative to arthrodesis for management of ankle arthritis. What is the outcome of total ankle arthroplasty implants currently in use? We conducted a systematic literature search of studies reporting on the outcome of total ankle arthroplasty. We included peer-reviewed studies reporting on at least 20 total ankle arthroplasties with currently used implants, with a minimum followup of 2 years. The Coleman Methodology Score was used to evaluate the quality of the studies. Thirteen Level IV studies of overall good quality reporting on 1105 total ankle arthroplasties (234 Agility, 344 STAR, 153 Buechel-Pappas, 152 HINTEGRA, 98 Salto, 70 TNK, 54 Mobility) were included. Residual pain was common (range, 27%-60%), superficial wound complications occurred in 0% to 14.7%, deep infections occurred in 0% to 4.6% of ankles, and ankle function improved after total ankle arthroplasty. The overall failure rate was approximately 10% at 5 years with a wide range (range, 0%-32%) between different centers. Superiority of an implant design over another cannot be supported by the available data. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

BACKGROUND: Several studies have shown mechanical alignment influences the outcome of TKA. Robotic systems have been developed to improve the precision and accuracy of achieving component position and mechanical alignment. QUESTIONS/PURPOSES: We determined whether robotic-assisted implantation for TKA (1) improved clinical outcome; (2) improved mechanical axis alignment and implant inclination in the coronal and sagittal planes; (3) improved the balance (flexion and extension gaps); and (4) reduced complications, postoperative drainage, and operative time when compared to conventionally implanted TKA over an intermediate-term (minimum 3-year) followup period. METHODS: We prospectively randomized 100 patients who underwent unilateral TKA into one of two groups: 50 using a robotic-assisted procedure and 50 using conventional manual techniques. Outcome variables considered were postoperative ROM, WOMAC scores, Hospital for Special Surgery (HSS) knee scores, mechanical axis alignment, flexion/extension gap balance, complications, postoperative drainage, and operative time. Minimum followup was 41 months (mean, 65 months; range, 41-81 months). RESULTS: There were no differences in postoperative ROM, WOMAC scores, and HSS knee scores. The robotic-assisted group resulted in no mechanical axis outliers (> ± 3° from neutral) compared to 24% in the conventional group. There were fewer robotic-assisted knees where the flexion gap exceeded the extension gap by 2 mm. The robotic-assisted procedures took an average of 25 minutes longer than the conventional procedures but had less postoperative blood drainage. There were no differences in complications between groups. CONCLUSIONS: Robotic-assisted TKA appears to reduce the number of mechanical axis alignment outliers and improve the ability to achieve flexion-extension gap balance, without any differences in clinical scores or complications when compared to conventional manual techniques.

Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.

BACKGROUND: To treat the coagulopathy of trauma, some have suggested early and aggressive use of cryoprecipitate as a source of fibrinogen. Our objective was to determine whether increased ratios of fibrinogen to red blood cells (RBCs) decreased mortality in combat casualties requiring massive transfusion. METHODS: We performed a retrospective chart review of 252 patients at a U.S. Army combat support hospital who received a massive transfusion (>or=10 units of RBCs in 24 hours). The typical amount of fibrinogen within each blood product was used to calculate the fibrinogen-to-RBC (F:R) ratio transfused for each patient. Two groups of patients who received either a low (<0.2 g fibrinogen/RBC Unit) or high (>or=0.2 g fibrinogen/RBC Unit) F:R ratio were identified. Mortality rates and the cause of death were compared between these groups, and logistic regression was used to determine if the F:R ratio was independently associated with survival. RESULTS: Two-hundred and fifty-two patients who received a massive transfusion with a mean (SD) ISS of 21 (+/-10) and an overall mortality of 75 of 252 (30%) were included. The mean (SD) F:R ratios transfused for the low and high groups were 0.1 grams/Unit (+/-0.06), and 0.48 grams/Unit (+/-0.2), respectively (p < 0.001). Mortality was 27 of 52 (52%) and 48 of 200 (24%) in the low and high F:R ratio groups respectively (p < 0.001). Additional variables associated with survival were admission temperature, systolic blood pressure, hemoglobin, International Normalized Ratio (INR), base deficit, platelet concentration and Combined Injury Severity Score (ISS). Upon logistic regression, the F:R ratio was independently associated with mortality (odds ratio 0.37, 95% confidence interval 0.171-0.812, p = 0.013). The incidence of death from hemorrhage was higher in the low F:R group, 23/27 (85%), compared to the high F:R group, 21/48 (44%) (p < 0.001). CONCLUSIONS: In patients with combat-related trauma requiring massive transfusion, the transfusion of an increased fibrinogen: RBC ratio was independently associated with improved survival to hospital discharge, primarily by decreasing death from hemorrhage. Prospective studies are needed to evaluate the best source of fibrinogen and the optimal empiric ratio of fibrinogen to RBCs in patients requiring massive transfusion.

BACKGROUND: Postamputation neuroma pain can prevent comfortable prosthesis wear in patients with limb amputations, and currently available treatments are not consistently effective. Targeted muscle reinnervation (TMR) is a decade-old technique that employs a series of novel nerve transfers to permit intuitive control of upper-limb prostheses. Clinical experience suggests that it may also serve as an effective therapy for postamputation neuroma pain; however, this has not been explicitly studied. QUESTIONS/PURPOSES: We evaluated the effect of TMR on residual limb neuroma pain in upper-extremity amputees. METHODS: We conducted a retrospective medical record review of all 28 patients treated with TMR from 2002 to 2012 at Northwestern Memorial Hospital/Rehabilitation Institute of Chicago (Chicago, IL, USA) and San Antonio Military Medical Center (San Antonio, TX, USA). Twenty-six of 28 patients had sufficient (> 6 months) followup for study inclusion. The amputation levels were shoulder disarticulation (10 patients) and transhumeral (16 patients). All patients underwent TMR for the primary purpose of improved myoelectric control. Of the 26 patients included in the study, 15 patients had evidence of postamputation neuroma pain before undergoing TMR. RESULTS: Of the 15 patients presenting with neuroma pain before TMR, 14 experienced complete resolution of pain in the transferred nerves, and the remaining patient's pain improved (though did not resolve). None of the patients who presented without evidence of postamputation neuroma pain developed neuroma pain after the TMR procedure. All 26 patients were fitted with a prosthesis, and 23 of the 26 patients were able to operate a TMR-controlled prosthesis. CONCLUSIONS: None of the 26 patients who underwent TMR demonstrated evidence of new neuroma pain after the procedure, and all but one of the 15 patients who presented with preoperative neuroma pain experienced complete relief of pain in the distribution of the transferred nerves. TMR offers a novel and potentially more effective therapy for the management of neuroma pain after limb amputation.

The secosteroid hormone, 1,25-dihydroxyvitamin D [1,25(OH)2D], plays a crucial role in normal bone growth, calcium metabolism, and tissue differentiation. The key step in the biosynthesis of 1,25(OH)2D is its 1 alpha-hydroxylation from 25-hydroxyvitamin D (25-OHD) in the kidney. Because its expression in the kidney is very low, we cloned and sequenced cDNA for 25-OHD-1 alpha-hydroxylase (P450c1 alpha) from human keratinocytes, in which 1 alpha-hydroxylase activity and mRNA expression can be induced to be much greater. P450c1 alpha mRNA was expressed at much lower levels in human kidney, brain, and testis. Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. The identity of the 1,25(OH)2D3 product synthesized in transfected cells was confirmed by HPLC and gas chromatography-mass spectrometry. The gene encoding P450c1 alpha was localized to chromosome 12, where the 1 alpha-hydroxylase deficiency syndrome, vitamin D-dependent rickets type 1 (VDDR-1), has been localized. Primary cultures of human adult and neonatal keratinocytes exhibit abundant 1 alpha-hydroxylase activity, whereas those from a patient with VDDR-1 lacked detectable activity. Keratinocyte P450c1 alpha cDNA from the patient with VDDR-1 contained deletion/frameshift mutations either at codon 211 or at codon 231, indicating that the patient was a compound heterozygote for two null mutations. These findings establish the molecular genetic basis of VDDR-1, establish a novel means for its study in keratinocytes, and provide the sequence of the key enzyme in the biological activation of vitamin D.

BACKGROUND: Optimal treatment remains uncertain for patients with cognitive impairment that persists or returns after standard IV antibiotic therapy for Lyme disease. METHODS: Patients had well-documented Lyme disease, with at least 3 weeks of prior IV antibiotics, current positive IgG Western blot, and objective memory impairment. Healthy individuals served as controls for practice effects. Patients were randomly assigned to 10 weeks of double-masked treatment with IV ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome was neurocognitive performance at week 12-specifically, memory. Durability of benefit was evaluated at week 24. Group differences were estimated according to longitudinal mixed-effects models. RESULTS: After screening 3368 patients and 305 volunteers, 37 patients and 20 healthy individuals enrolled. Enrolled patients had mild to moderate cognitive impairment and marked levels of fatigue, pain, and impaired physical functioning. Across six cognitive domains, a significant treatment-by-time interaction favored the antibiotic-treated group at week 12. The improvement was generalized (not specific to domain) and moderate in magnitude, but it was not sustained to week 24. On secondary outcome, patients with more severe fatigue, pain, and impaired physical functioning who received antibiotics were improved at week 12, and this was sustained to week 24 for pain and physical functioning. Adverse events from either the study medication or the PICC line were noted among 6 of 23 (26.1%) patients given IV ceftriaxone and among 1 of 14 (7.1%) patients given IV placebo; these resolved without permanent injury. CONCLUSION: IV ceftriaxone therapy results in short-term cognitive improvement for patients with posttreatment Lyme encephalopathy, but relapse in cognition occurs after the antibiotic is discontinued. Treatment strategies that result in sustained cognitive improvement are needed.

OBJECTIVE: Pain commonly coexists with depression, but its impact on treatment outcomes has not been well studied. Therefore, we prospectively evaluated the impact of comorbid pain on depression treatment response and health-related quality of life. METHODS: We analyzed data from the ARTIST study, a randomized controlled trial with naturalistic follow-up conducted in 37 primary care clinics. Participants were 573 clinically depressed patients randomized to one of three selective serotonin reuptake inhibitor (SSRI) antidepressants: fluoxetine, paroxetine, or sertraline. Depression as assessed by the Symptom Checklist-20 (SCL-20) was the primary outcome. Secondary outcomes included pain and health-related quality of life. RESULTS: Pain was reported by more than two thirds of depressed patients at baseline, with the severity of pain mild in 25% of patients, moderate in 30%, and severe in 14%. After 3 months of antidepressant therapy, 24% of patients had a poor depression treatment response (ie, SCL-20 >1.3). Multivariate odds ratios for poor treatment response were 1.5 (95% confidence interval, 0.8-3.2) for mild pain, 2.0 (1.1-4.0) for moderate pain, and 4.1 (1.9-8.8) for severe pain compared with those without pain. Increasing pain severity also had an adverse impact on outcomes in multiple domains of health-related quality of life. CONCLUSIONS: Pain is present in two thirds of depressed primary care patients begun on antidepressant therapy, and the severity of pain is a strong predictor of poor depression and health-related quality of life outcomes at 3 months. Better recognition, assessment, and treatment of comorbid pain may enhance outcomes of depression therapy.