Mycobacterium tuberculosis sternal wound infection after open heart surgery: a case report and review of the literature

Tuberculous osteomyelitis of sternum after open heart surgery is a rare disease entity. We report a case of wound infection with osteomyelitis caused by Mycobacterium tuberculosis in a patient with diabetic nephropathy, requiring peritoneal dialysis after coronary artery bypass grafting, who was successfully treated with antituberculous agents and surgical debridement. In addition, we provide a literature review on reported cases of tuberculous sternal osteomyelitis and mediastinitis after open heart surgery, and discuss about the risk factors, clinical features, and treatment of this infection.     

Till death do us part: getting married at the end of life

At the end of life, patients often reflect on the meaning of their lives and decide how to best take advantage of the remaining time to accomplish their life goals. We report the case of a patient with advanced cancer who got married in our acute palliative care unit weeks before her death. Our interdisciplinary team was able to support her physically and emotionally, thereby assisting her in achieving her life goals. The wedding gave her the opportunity to acquire further meaning in life, deepen her connection with her loved ones, and enhance her sense of dignity, self-worth, and pride. It also was associated with a significant improvement in her symptoms and had a positive effect on the health care team.?This example illustrates the effectiveness of a palliative care team in helping patients?to?achieve their life goals and supporting their families during a time when two major life?events, marriage and end of life, occur concurrently.     

HPA-1a antibody potency and bioactivity do not predict severity of fetomaternal alloimmune thrombocytopenia

BACKGROUND: The antenatal management of fetomaternal alloimmune thrombocytopenia (FMAIT) due to HPA-1a antibodies remains controversial, and a test identifying pregnancies that do not require therapy would be of clinical value. STUDY DESIGN AND METHODS: The statistical correlation was analyzed between clinical outcome and 1) anti-HPA-1a potency in maternal serum samples determined by a monoclonal antibody immobilization of platelet (PLT) antigen assay with an international anti-HPA-1a potency standard and 2) anti-HPA-1a biological activity measured by a monocyte chemiluminescence (CL) assay. RESULTS: A total of 133 pregnancies with FMAIT due to anti-HPA-1a were analyzed. In 97 newly diagnosed cases, there was no difference in antibody potency or CL signal between cases with intracranial hemorrhage (ICH; n = 15), those with no ICH but a PLT count of less than 20 x 10(9) per L (n = 52), and those with a PLT count of at least 20 x 10(9) per L (n = 30). In 22 previously known pregnancies, the positive predictive value of maternal anti-HPA-1a of greater than 30 IU per mL for a PLT count of less than 20 x 10(9) per L was 90 percent, but the negative predictive value was only 66 percent. Antibody potency tended to stay stable throughout pregnancy (n = 16) and from one pregnancy to the next (n = 16). CONCLUSION: Neither severe thrombocytopenia nor ICH in HPA-1a-alloimmunized pregnancies can be predicted with sufficient sensitivity and specificity for clinical application from maternal anti-HPA-1a potency or bioactivity.     

Regulatory guidelines do not accurately predict tolvaptan and metabolite interactions at BCRP,OATP1B1, and OAT3 transporters

Tolvaptan (TLV) was US Food and Drug Administration (FDA)‐approved for the indication to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease in 2018. In vitro, TLV was a breast cancer resistance protein (BCRP) inhibitor, whereas the oxobutyric acid metabolite of TLV (DM‐4013) was an inhibitor of organic anion transport polypeptide (OATP)1B1 and organic anion transporter (OAT)3. Based on the 2017 FDA guidance, potential for clinically relevant inhibition at these transporters was indicated for the highest TLV regimen. Consequently, two postmarketing clinical trials in healthy subjects were required. In trial 1, 5 mg rosuvastatin calcium (BCRP and OATP1B1 substrate) was administered alone, with 90 mg TLV or 48 h following 7 days of once daily 300 mg TLV (i.e., in the presence of DM‐4103). In trial 2, 40 mg furosemide (OAT3 substrate) was administered alone and in presence of DM‐4103. For BCRP, rosuvastatin geometric mean ratios (90% confidence intervals [CIs]) for maximum plasma concentration (C_max) were 1.54 (90% CI 1.26–1.88) and for area under the concentration‐time curve from time 0 to the time of the last measurable concentration (AUC_t) were 1.69 (90% CI 1.34–2.14), indicating no clinically significant interaction. DM‐4103 produced no clinically meaningful changes in rosuvastatin or furosemide concentrations, indicating no inhibition at OATP1B1 or OAT3. The BCRP prediction assumed the drug dose is completely soluble in 250 ml; TLV has solubility of ~0.01 g/250 ml. For OATP1B1/OAT3, if fraction unbound for plasma protein binding (PPB) is less than 1%, then 1% is assumed. DM‐4103 has PPB greater than 99.8%. Use of actual drug substance solubility and unbound fraction in plasma would have produced predictions consistent with the clinical results.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The US Food and Drug Administration (FDA) created a guidance for estimating the potential for clinically relevant drug‐drug interactions (DDIs) at BCRP, OATP1B1, OAT3, and other transporters. The predictions use various assumptions. For example, for BCRP, it is assumed that inhibitory drug is completely soluble in 250 ml. For OATP1B1 and OAT3, if plasma protein binding for inhibitor is greater than 99%, then fraction unbound is set to 1%.

• WHAT QUESTION DID THIS STUDY ADDRESS?

These studies addressed if the predictions for clinically relevant DDIs at BCRP for tolvaptan and at OATP1B1 and OAT3 for the oxobutyric acid metabolite were correct and interactions were observed.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

As there were no clinically relevant interactions, the results support the consideration of drug solubility for BCRP and actual plasma protein binding for OATP1B1 and OAT3 in the predictions of clinically relevant DDIs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Assumptions used in the prediction of clinically relevant DDIs would be revised.     

Self-care at the end of life in patients with heart failure

Promoting adherence to self-care illness management strategies among patients with heart failure (HF) has been associated with a number of positive health outcomes. Yet, little is known about health outcomes related to self-care in the "sickest of the sick"-those patients with advanced HF who are approaching the end of life. Clinicians and researchers must determine how self-care interventions are defined in the advanced HF population. For example, what is meant by self-care illness management in patients who are symptomatic with exertion may differ from that of patients who are predominantly symptomatic at rest. Our challenge is to develop the simplest, least burdensome self-care illness management interventions that target the most meaningful outcomes for patients, their families, and the healthcare system.     

Prolongation of the QT interval in heart failure occurs at low but not at high heart rates

Abnormal left ventricular structure and function as in, for example, left ventricular hypertrophy or chronic heart failure, is associated with sudden cardiac death and, when the ejection fraction is depressed, with prolongation of the QT interval. The dependence on heart rate of QT interval prolongation in these conditions, and the relationship of any abnormalities either to deranged autonomic nervous system function or to an adverse prognosis, has not been well studied. We therefore investigated (1) the dependence on heart rate of the QT interval, and (2) the relationship between both QT interval and the QT/heart rate slope and markers of adverse prognosis in these two conditions. The QT interval was measured at rest and during exercise in 34 subjects with heart failure, 16 subjects with left ventricular hypertrophy and 16 age-matched controls with normal left ventricular structure and function. QTc (corrected QT) intervals at rest were significantly longer in heart failure patients (471+/-10 ms) than in controls (421+/-6 ms) or in subjects with hypertrophy (420+/-6 ms) (P<0.05). At peak exercise, despite the attainment of similar heart rates, the QT intervals no longer differed from each other, being 281+/-7 ms for controls, 296+/-11 ms in hypertrophy and 303+/-10 ms in heart failure (no significant difference). The QT/heart rate slope was significantly increased in heart failure [2.3+/-0.1 ms.(beats/min)(-1)] compared with controls [1.55+/-0.06 ms.(beats/min)(-1)] and hypertrophy [1. 66+/-0.1 ms.(beats/min)(-1)] (P<0.001). In left ventricular hypertrophy, despite animal data suggesting that QT interval prolongation should occur, no abnormalities were found in QT intervals at rest or during exercise. The QT/heart rate slope did not relate to any markers for an adverse prognosis, except that of prolongation of QT interval. Long QT intervals were associated principally with impairment of left ventricular systolic function. Our data emphasize the dynamic nature of the QT interval abnormalities found in heart failure.     

Pressure pain thresholds fluctuate with,but do not usefully predict,the clinical course of painful temporomandibular disorder

Central sensitization elicits pain hypersensitivity and is thought to be causally implicated in painful temporomandibular disorder (TMD). This causal inference is based on cross-sectional evidence that people with TMD have greater sensitivity than controls to noxious stimuli. We tested this inference in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study of 3258 adults with no lifetime history of TMD when enrolled (visit 1). During 5 years of follow-up, 1 group labeled “persistent TMD cases” (n = 72) developed first-onset TMD by visit 2 that persisted ?6 months until visit 3. Another group labeled “transient TMD cases” (n = 75) developed first-onset TMD at visit 2, which resolved by visit 3. Randomly sampled “controls” (n = 126) remained TMD-free throughout all 3 visits. At each visit, pressure pain thresholds (PPTs) were measured by algometry at 10 cranial and bodily sites. In persistent TMD case patients, mean PPTs reduced 43 kPa (P < .0001) between visits 1 and 2 and thereafter did not change significantly. In transient TMD case patients, mean PPTs reduced 41 kPa (P < .001) between visits 1 and 2, and then increased 20 kPa (P < .001) by visit 3. These patterns were similar after excluding cranial sites symptomatic for TMD. Importantly, visit 1 PPTs had no clinically useful prognostic value in predicting first-onset TMD (odds ratio [OR] = 1.07, P = .15). Among first-onset case patients, visit 2 PPTs were modest predictors of persistent TMD (OR = 1.36, P = .002). In this longitudinal study, PPTs reduced when TMD developed then rebounded when TMD resolved. However, premorbid PPTs poorly predicted TMD incidence, countering the hypothesis that PPTs signify mechanisms causing first-onset TMD.     

Case of the month: "bugs are eating my soul"--sternal abscess, osteomyelitis, and mediastinitis complicating a closed sternal fracture

Wound complications of closed sternal fracture are rare, but may have serious consequences if not effectively managed. We report a case of a patient who presented to the emergency department with a sternal abscess, osteomyelitis, and mediastinitis complicating a closed sternal fracture. It is hypothesised that in our patient bacteraemia post intravenous drug use resulted in seeding of the haematoma with Staphylococcus aureus. Early diagnosis and a multidisciplinary team effort were important in ensuring a favourable outcome.     

Managing grief and depression at the end of life

Psychological distress is common in terminally ill persons and can be a source of great suffering. Grief is an adaptive, universal, and highly personalized response to the multiple losses that occur at the end of life. This response may be intense early on after a loss manifesting itself physically, emotionally, cognitively, behaviorally, and spiritually; however, the impact of grief on daily life generally decreases with time. Although pharmacologic interventions are not warranted for uncomplicated grief, physicians are encouraged to support patients by acknowledging their grief and encouraging the open expression of emotions. It is important for the physician to distinguish uncomplicated grief reactions from more disabling psychiatric disorders such as major depression. The symptoms of grief may overlap with those of major depression or a terminal illness or its treatment; however, grief is a distinct entity. Feelings of pervasive hopelessness, helplessness, worthlessness, guilt, lack of pleasure, and suicidal ideation are present in patients with depression, but not in those experiencing grief. Psychotherapy and antidepressant medications reduce symptoms of distress and improve quality of life for patients with depression. Physicians may consider psychostimulants, such as methylphenidate, for patients who have depression with a life expectancy of only days to weeks.     

To stent or not to stent: an evidence-based approach to palliative procedures at the end of life

Patients near the end of life often undergo invasive procedures, such as biliary stenting for obstructive jaundice, with the intent of relieving symptoms. We describe a case in which the medical team and a patient and family are considering a second palliative biliary stent despite the patient's limited life expectancy. We review available evidence to inform the decision, focusing on the specific question of whether the benefits of palliative biliary stents in patients with advanced cancer outweigh the risks. We then apply the evidence to the issue of how the primary and/or palliative care team and the interventionist communicate with patients and their families about the risks and benefits of palliative procedures. Review of the evidence found several prospective case series without control groups that measured patient-centered outcomes. Studies had high attrition rates, results for improvements in symptoms and quality of life were mixed, and rates of complications and short-term mortality were high. In conclusion, the limited evidence does not support that the benefits of palliative biliary stents in this population outweigh the risks. We propose that primary care teams consider and discuss the larger picture of the goals of care with patients and families when considering offering these procedures, as well as benefits and potential harms, and consider involving palliative care services early, before consultation with an interventionist.