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The New England Journal of Medicine Jul 2016A 22-year-old woman reports having hirsutism and irregular menses. She describes unpredictable and infrequent menses (five or six per year) since menarche at 11 years of... (Review)
Review
A 22-year-old woman reports having hirsutism and irregular menses. She describes unpredictable and infrequent menses (five or six per year) since menarche at 11 years of age. Dark, coarse facial hair began to develop at 13 years of age. The symptoms worsened after she gained weight in college. The physical examination includes a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 29, blood pressure of 135/85 mm Hg, and moderate hirsutism without virilization. Laboratory tests reveal a total testosterone level of 65 ng per deciliter (2.3 nmol per liter) (assay reference range, 14 to 53 ng per deciliter [0.5 to 1.8 nmol per liter]), calculated free testosterone level of 15.3 pg per milliliter (53.1 pmol per liter) (assay reference range, 0.6 to 6.8 pg per milliliter [2.1 to 23.6 pmol per liter]), and glycated hemoglobin level of 5.7% (normal value, ≤5.6%). How should this case be evaluated and managed?
Topics: Contraceptives, Oral, Combined; Female; Hirsutism; Humans; Polycystic Ovary Syndrome; Young Adult
PubMed: 27406348
DOI: 10.1056/NEJMcp1514916 -
The New England Journal of Medicine May 2017Obesity causes frailty in older adults; however, weight loss might accelerate age-related loss of muscle and bone mass and resultant sarcopenia and osteopenia. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Obesity causes frailty in older adults; however, weight loss might accelerate age-related loss of muscle and bone mass and resultant sarcopenia and osteopenia.
METHODS
In this clinical trial involving 160 obese older adults, we evaluated the effectiveness of several exercise modes in reversing frailty and preventing reduction in muscle and bone mass induced by weight loss. Participants were randomly assigned to a weight-management program plus one of three exercise programs - aerobic training, resistance training, or combined aerobic and resistance training - or to a control group (no weight-management or exercise program). The primary outcome was the change in Physical Performance Test score from baseline to 6 months (scores range from 0 to 36 points; higher scores indicate better performance). Secondary outcomes included changes in other frailty measures, body composition, bone mineral density, and physical functions.
RESULTS
A total of 141 participants completed the study. The Physical Performance Test score increased more in the combination group than in the aerobic and resistance groups (27.9 to 33.4 points [21% increase] vs. 29.3 to 33.2 points [14% increase] and 28.8 to 32.7 points [14% increase], respectively; P=0.01 and P=0.02 after Bonferroni correction); the scores increased more in all exercise groups than in the control group (P<0.001 for between-group comparisons). Peak oxygen consumption (milliliters per kilogram of body weight per minute) increased more in the combination and aerobic groups (17.2 to 20.3 [17% increase] and 17.6 to 20.9 [18% increase], respectively) than in the resistance group (17.0 to 18.3 [8% increase]) (P<0.001 for both comparisons). Strength increased more in the combination and resistance groups (272 to 320 kg [18% increase] and 288 to 337 kg [19% increase], respectively) than in the aerobic group (265 to 270 kg [4% increase]) (P<0.001 for both comparisons). Body weight decreased by 9% in all exercise groups but did not change significantly in the control group. Lean mass decreased less in the combination and resistance groups than in the aerobic group (56.5 to 54.8 kg [3% decrease] and 58.1 to 57.1 kg [2% decrease], respectively, vs. 55.0 to 52.3 kg [5% decrease]), as did bone mineral density at the total hip (grams per square centimeter; 1.010 to 0.996 [1% decrease] and 1.047 to 1.041 [0.5% decrease], respectively, vs. 1.018 to 0.991 [3% decrease]) (P<0.05 for all comparisons). Exercise-related adverse events included musculoskeletal injuries.
CONCLUSIONS
Of the methods tested, weight loss plus combined aerobic and resistance exercise was the most effective in improving functional status of obese older adults. (Funded by the National Institutes of Health; LITOE ClinicalTrials.gov number, NCT01065636 .).
Topics: Aged; Body Composition; Bone Density; Combined Modality Therapy; Exercise; Exercise Therapy; Female; Frail Elderly; Humans; Male; Obesity; Oxygen Consumption; Resistance Training; Single-Blind Method; Weight Loss
PubMed: 28514618
DOI: 10.1056/NEJMoa1616338 -
The New England Journal of Medicine Apr 2019Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors.
BACKGROUND
Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors.
METHODS
We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin).
RESULTS
Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.
CONCLUSIONS
In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).
Topics: Acute Disease; Aged; Aged, 80 and over; Atrial Fibrillation; Coagulants; Factor Xa; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intracranial Hemorrhages; Male; ROC Curve; Recombinant Proteins
PubMed: 30730782
DOI: 10.1056/NEJMoa1814051 -
The New England Journal of Medicine Dec 2015Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.
METHODS
Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.
RESULTS
Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported.
CONCLUSIONS
Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).
Topics: Administration, Oral; Aged; Antidotes; Blood Coagulation; Double-Blind Method; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Peptide Fragments; Protein Precursors; Prothrombin; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban
PubMed: 26559317
DOI: 10.1056/NEJMoa1510991 -
The New England Journal of Medicine Jul 2020Vitamin D metabolites support innate immune responses to . Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vitamin D metabolites support innate immune responses to . Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis infection are lacking.
METHODS
We randomly assigned children who had negative results for infection according to the QuantiFERON-TB Gold In-Tube assay (QFT) to receive a weekly oral dose of either 14,000 IU of vitamin D or placebo for 3 years. The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children. Secondary outcomes included the serum 25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events.
RESULTS
A total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children with a valid QFT result at the end of the trial, the percentage with a positive result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87 to 1.38; P = 0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of adverse events did not differ significantly between the two groups.
CONCLUSIONS
Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D-deficient schoolchildren in Mongolia. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.).
Topics: Child; Cholecalciferol; Dietary Supplements; Double-Blind Method; Female; Follow-Up Studies; Humans; Incidence; Latent Tuberculosis; Male; Mycobacterium tuberculosis; Respiratory Tract Infections; Treatment Failure; Tuberculin Test; Vitamin D; Vitamins
PubMed: 32706534
DOI: 10.1056/NEJMoa1915176 -
JAMA Surgery Feb 2017Postoperative pulmonary complications (PPCs), a leading cause of poor surgical outcomes, are heterogeneous in their pathophysiology, severity, and reporting accuracy. (Observational Study)
Observational Study
Postoperative Pulmonary Complications, Early Mortality, and Hospital Stay Following Noncardiothoracic Surgery: A Multicenter Study by the Perioperative Research Network Investigators.
IMPORTANCE
Postoperative pulmonary complications (PPCs), a leading cause of poor surgical outcomes, are heterogeneous in their pathophysiology, severity, and reporting accuracy.
OBJECTIVE
To prospectively study clinical and radiological PPCs and respiratory insufficiency therapies in a high-risk surgical population.
DESIGN, SETTING, AND PARTICIPANTS
We performed a multicenter prospective observational study in 7 US academic institutions. American Society of Anesthesiologists physical status 3 patients who presented for noncardiothoracic surgery requiring 2 hours or more of general anesthesia with mechanical ventilation from May to November 2014 were included in the study. We hypothesized that PPCs, even mild, would be associated with early postoperative mortality and use of hospital resources. We analyzed their association with modifiable perioperative variables.
EXPOSURE
Noncardiothoracic surgery.
MAIN OUTCOMES AND MEASURES
Predefined PPCs occurring within the first 7 postoperative days were prospectively identified. We used bivariable and logistic regression analyses to study the association of PPCs with ventilatory and other perioperative variables.
RESULTS
This study included 1202 patients who underwent predominantly abdominal, orthopedic, and neurological procedures. The mean (SD) age of patients was 62.1 (13.8) years, and 636 (52.9%) were men. At least 1 PPC occurred in 401 patients (33.4%), mainly the need for prolonged oxygen therapy by nasal cannula (n = 235; 19.6%) and atelectasis (n = 206; 17.1%). Patients with 1 or more PPCs, even mild, had significantly increased early postoperative mortality, intensive care unit (ICU) admission, and ICU/hospital length of stay. Significant PPC risk factors included nonmodifiable (emergency [yes vs no]: odds ratio [OR], 4.47, 95% CI, 1.59-12.56; surgical site [abdominal/pelvic vs nonabdominal/pelvic]: OR, 2.54, 95% CI, 1.67-3.89; and age [in years]: OR, 1.03, 95% CI, 1.02-1.05) and potentially modifiable (colloid administration [yes vs no]: OR, 1.75, 95% CI, 1.03-2.97; preoperative oxygenation: OR, 0.86, 95% CI, 0.80-0.93; blood loss [in milliliters]: OR, 1.17, 95% CI, 1.05-1.30; anesthesia duration [in minutes]: OR, 1.14, 95% CI, 1.05-1.24; and tidal volume [in milliliters per kilogram of predicted body weight]: OR, 1.12, 95% CI, 1.01-1.24) factors.
CONCLUSIONS AND RELEVANCE
Postoperative pulmonary complications are common in patients with American Society of Anesthesiologists physical status 3, despite current protective ventilation practices. Even mild PPCs are associated with increased early postoperative mortality, ICU admission, and length of stay (ICU and hospital). Mild frequent PPCs (eg, atelectasis and prolonged oxygen therapy need) deserve increased attention and intervention for improving perioperative outcomes.
Topics: Abdomen; Age Factors; Aged; Aged, 80 and over; Anesthesia; Blood Loss, Surgical; Colloids; Emergencies; Female; Humans; Intensive Care Units; Length of Stay; Lung Diseases; Male; Middle Aged; Neurosurgical Procedures; Orthopedic Procedures; Oxygen Inhalation Therapy; Pelvis; Postoperative Complications; Preoperative Care; Prospective Studies; Respiration, Artificial; Respiratory Insufficiency; Risk Factors; Tidal Volume; Time Factors
PubMed: 27829093
DOI: 10.1001/jamasurg.2016.4065 -
The New England Journal of Medicine Apr 2023A 48-year-old man with long-standing type 2 diabetes mellitus (recent glycated hemoglobin level, 6.5%) and chronic kidney disease (baseline creatinine level, 3.3 mg per...
A 48-year-old man with long-standing type 2 diabetes mellitus (recent glycated hemoglobin level, 6.5%) and chronic kidney disease (baseline creatinine level, 3.3 mg per deciliter [292 mol per liter]; glomerular filtration rate, 24 ml per minute per 1.73 m of body-surface area) presented to his primary care physician with a 3-month history of numbness, tingling, and faint violaceous discoloration of the tips of multiple fingers and toes. His physical examination showed reduced light-touch sensation in a glove-and-stocking distribution; the radial and pedal pulses were palpable. The vitamin B level was 260 pg per milliliter (192 pmol per liter; normal range, 190 to 950 pg per milliliter [140 to 701 pmol per liter]). He did not smoke tobacco, drink alcohol, or use illicit drugs. One month later, a nontraumatic wound developed on the left foot. The ankle–brachial index (ABI) was 1.2 on both sides (normal range, 0.91 to 1.3). Wound care was initiated for a presumed neuropathic ulcer.
PubMed: 37018496
DOI: 10.1056/NEJMcps2210419