Objective
To develop recommendations for prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP).
Methods
We conducted a systematic review to synthesize the evidence for the benefits ...and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long‐term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long‐term GC treatment, as well as in special populations of long‐term GC users.
Results
Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate‐to‐high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high‐dose GC treatment, are also made.
Conclusion
This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision‐making process that accounts for patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
The Ras GTPases are frequently mutated in human cancer, and, although the Raf kinases are essential effectors of Ras signaling, the tumorigenic properties of specific Ras-Raf complexes are not well ...characterized. Here, we examine the ability of individual Ras and Raf proteins to interact in live cells using bioluminescence resonance energy transfer (BRET) technology. We find that C-Raf binds all mutant Ras proteins with high affinity, whereas B-Raf exhibits a striking preference for mutant K-Ras. This selectivity is mediated by the acidic, N-terminal segment of B-Raf and requires the K-Ras polybasic region for high-affinity binding. In addition, we find that C-Raf is critical for mutant H-Ras-driven signaling and that events stabilizing B-Raf/C-Raf dimerization, such as Raf inhibitor treatment or certain B-Raf mutations, can allow mutant H-Ras to engage B-Raf with increased affinity to promote tumorigenesis, thus revealing a previously unappreciated role for C-Raf in potentiating B-Raf function.
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•C-Raf binds all Ras proteins equivalently, but B-Raf exhibits selectivity for K-Ras•Raf N-terminal segments and Ras HVR sequences determine binding preferences•C-Raf is critical for downstream transmission of H-Ras-driven signaling•Events that increase B-Raf/C-Raf dimerization augment the B-Raf/H-Ras interaction
The Raf kinases bind to active Ras proteins and function to transmit signals that control cell growth and tumorigenesis. The study by Terrell et al. reveals distinct binding preferences between individual Ras and Raf family members and identifies events that can alter these interactions to upregulate Ras-driven cancer signaling.
Objective
To develop recommendations for prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP).
Methods
We conducted a systematic review to synthesize the evidence for the benefits ...and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long‐term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long‐term GC treatment, as well as in special populations of long‐term GC users.
Results
Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate‐to‐high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high‐dose GC treatment, are also made.
Conclusion
This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision‐making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
Objective Patients receiving interfacility transfer to a higher level of medical care for ruptured abdominal aortic aneurysms (rAAAs) are an important minority that are not well characterized and are ...typically omitted from outcomes and quality indicator studies. Our objective was to compare patients transferred for treatment of rAAAs with those treated without transfer, with particular emphasis on mortality and resource utilization. Methods We linked longitudinal data from 2005 to 2010 Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases and Emergency Department Databases from California, Florida, and New York. Patients were identified using International Classification of Diseases-Ninth Revision-Clinical Modification codes. Our main outcome variables were mortality, length of stay, and cost. Data included discharge information on the transfer-out and transfer-in hospital. We used univariate and multivariate analysis to identify variables independently associated with transfer and in-hospital mortality. Results Of 4439 rAAA patients identified with intent to treat, 847 (19.1%) were transferred before receiving operative repair. Of those transferred, 141 (17%) died without undergoing AAA repair. By multivariate analysis, increasing age in years (odds ratio OR 0.98; 95% confidence interval CI, 0.97-0.99; P < .001), private insurance vs Medicare (OR, 0.62; 95% CI, 0.47-0.80; P < .001), and increasing comorbidities as measured by the Elixhauser Comorbidity Index (OR, 0.90; 95% CI, 0.86-0.95; P < .001) were negatively associated with transfer. Weekend presentation (OR, 1.23; 95% CI, 1.02-1.47; P = .03) was positively associated with transfer. Transfer was associated with a lower operative mortality (adjusted OR, 0.81; 95% CI, 0.68-0.97; P < .02) but an increased overall mortality when including transferred patients who died without surgery (OR, 1.30; 95% CI, 1.05-1.60; P = .01). Among the transferred patients, there was no significant difference in travel distance between those who survived and those who died (median, 28.7 vs 25.8 miles; P = .07). Length of stay (median, 10 vs 9 days; P = .008), and hospital costs ($161,000 vs $146,000; P = .02) were higher for those transferred. Conclusions The survival advantage for patients transferred who received treatment was eclipsed by increased mortality of the transfer process. Including 17% of transferred patients who died without receiving definitive repair, mortality was increased for patients transferred for rAAA repair compared with those not transferred after adjusting for demographic, clinical, and hospital factors. Transferred patients used significantly more hospital resources. Improving systems and guidelines for interfacility transfer may further improve the outcomes for these patients and decrease associated hospital resource utilization.
Background It is unknown if initiation of a sodium-glucose cotransporter-2 inhibitor (SGLT-2i) is associated with changes in patient-reported health status outside of clinical trials. Methods and ...Results Using a prospective observational study design, adults with type 2 diabetes and cardiovascular disease were recruited from 14 US hospitals between November 2019 and December 2021 if they were new users of noninsulin antidiabetic medications. The primary outcome was change in 6-month diabetes treatment satisfaction. Secondary outcomes included diabetes-related symptom distress, diabetes-specific quality of life, and general health status for all patients and based on cardiovascular disease type. Inverse probability of treatment weight using propensity score was performed to compare outcome changes based on medication use. Of 887 patients (SGLT-2i: n=242) included in the inverse probability of treatment weight analyses, there was no difference in changes in treatment satisfaction in SGLT-2i users compared with other diabetes medication users (0.99 95% CI, -0.14 to 2.13 versus 1.54 1.08 to 2.00,
=0.38). Initiating an SGLT-2i versus other diabetes medications was associated with a greater reduction in ophthalmological symptoms (-3.09 95% CI, -4.99 to -1.18 versus -0.38 -1.54 to 0.77,
=0.018) but less improvement in hyperglycemia (1.08 -2.63 to 4.79 versus -3.60 -5.34 to -1.86,
=0.026). In subgroup analyses by cardiovascular disease type, SGLT-2i use was associated with a greater reduction in total diabetes symptom burden and neurological sensory symptoms in patients with heart failure. Conclusions Among patients with type 2 diabetes and cardiovascular disease, initiating an SGLT-2i was not associated with changes in diabetes treatment satisfaction, total diabetes symptoms, diabetes-specific quality of life, or general health status.
Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage disease caused by deficiency of ...β-N-acetylhexosaminidase (Hex). While untreated mice reach the humane endpoint by 4.1 months of age, mice treated by a single intracranial injection of vectors expressing human hexosaminidase may live a normal life span of 2 years. When treated with the same therapeutic vectors used in mice, two cats with SD lived to 7.0 and 8.2 months of age, compared with an untreated life span of 4.5 ± 0.5 months (n = 11). Because a pronounced humoral immune response to both the AAV1 vectors and human hexosaminidase was documented, feline cDNAs for the hexosaminidase α- and β-subunits were cloned into AAVrh8 vectors. Cats treated with vectors expressing feline hexosaminidase produced enzymatic activity >75-fold normal at the brain injection site with little evidence of an immune infiltrate. Affected cats treated with feline-specific vectors by bilateral injection of the thalamus lived to 10.4 ± 3.7 months of age (n = 3), or 2.3 times as long as untreated cats. These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research.
Progressive debilitating neurological defects characterize feline G(M1) gangliosidosis, a lysosomal storage disease caused by deficiency of lysosomal β-galactosidase. No effective therapy exists for ...affected children, who often die before age 5 years. An adeno-associated viral vector carrying the therapeutic gene was injected bilaterally into two brain targets (thalamus and deep cerebellar nuclei) of a feline model of G(M1) gangliosidosis. Gene therapy normalized β-galactosidase activity and storage throughout the brain and spinal cord. The mean survival of 12 treated G(M1) animals was >38 months, compared to 8 months for untreated animals. Seven of the eight treated animals remaining alive demonstrated normalization of disease, with abrogation of many symptoms including gait deficits and postural imbalance. Sustained correction of the G(M1) gangliosidosis disease phenotype after limited intracranial targeting by gene therapy in a large animal model suggests that this approach may be useful for treating the human version of this lysosomal storage disorder.
Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by defects in the β-subunit of β-N-acetylhexosaminidase (Hex), the enzyme that catabolizes GM2 ganglioside. Hex ...deficiency causes neuronal storage of GM2 and related glycoconjugates, resulting in progressive neurodegeneration and death, typically in infancy. No effective treatment exists for human patients. Adeno-associated virus (AAV) gene therapy led to improved clinical outcome and survival of SD cats treated before the onset of disease symptoms. Most human patients are diagnosed after clinical disease onset, so it is imperative to test AAV-gene therapy in symptomatic SD cats to provide a realistic indication of therapeutic benefits that can be expected in humans. In this study, AAVrh8 vectors injected into the thalamus and deep cerebellar nuclei of symptomatic SD cats resulted in widespread central nervous system enzyme distribution, although a substantial burden of storage material remained. Cats treated in the early symptomatic phase showed delayed disease progression and a significant survival increase versus untreated cats. Treatment was less effective when administered later in the disease course, although therapeutic benefit was still possible. Results are encouraging for the treatment of human patients and provide support for the development AAV-gene therapy for human SD.
About a third of tumors have activating mutations in
,
, or
, genes encoding guanosine triphosphatases (GTPases) of the RAS family. In these tumors, wild-type RAS cooperates with mutant RAS to ...promote downstream effector activation and cell proliferation and transformation, suggesting that upstream activators of wild-type RAS are important modulators of mutant RAS-driven oncogenesis. The guanine nucleotide exchange factor (GEF) SOS1 mediates KRAS-driven proliferation, but little is understood about the role of SOS2. We found that RAS family members have a hierarchical requirement for the expression and activity of SOS2 to drive cellular transformation. In mouse embryonic fibroblasts (MEFs), SOS2 critically mediated mutant KRAS-driven, but not HRAS-driven, transformation.
deletion reduced epidermal growth factor (EGF)-dependent activation of wild-type HRAS and phosphorylation of the kinase AKT in cells expressing mutant RAS isoforms. Assays using pharmacological inhibitors revealed a hierarchical requirement for signaling by phosphoinositide 3-kinase (PI3K) in promoting RAS-driven cellular transformation that mirrored the requirement for SOS2. KRAS-driven transformation required the GEF activity of SOS2 and was restored in
MEFs by expression of constitutively activated PI3K. Finally, CRISPR/Cas9-mediated deletion of
reduced EGF-stimulated AKT phosphorylation and synergized with MEK inhibition to revert the transformed phenotype of human
mutant pancreatic and lung tumor cells. These results indicate that SOS2-dependent PI3K signaling mediates mutant KRAS-driven transformation, revealing therapeutic targets in KRAS-driven cancers. Our data also reveal the importance of three-dimensional culture systems in investigating the mediators of mutant KRAS.
Spasmodic dysphonia (SD) is a neurological disorder of the voice where a patient's ability to speak is compromised due to involuntary contractions of the intrinsic laryngeal muscles. Since the 1980s, ...SD has been treated with botulinum toxin A (BTX) injections into the throat. This therapy is limited by the delayed-onset of benefits, wearing-off effects, and repeated injections required every 3 months. In a patient with essential tremor (ET) and coincident SD, the authors set out to quantify the effects of thalamic deep brain stimulation (DBS) on vocal function while investigating the underlying motor thalamic circuitry. A 79-year-old right-handed woman with ET and coincident adductor SD was referred to our neurosurgical team. While primarily treating her limb tremor, the authors studied the effects of unilateral, thalamic DBS on vocal function using the Unified Spasmodic Dysphonia Rating Scale (USDRS) and voice-related quality of life (VRQOL). Since dystonia is increasingly being considered a multinodal network disorder, an anterior trajectory into the left thalamus was deliberately chosen such that the proximal contacts of the electrode were in the ventral oralis anterior (Voa) nucleus (pallidal outflow) and the distal contacts were in the ventral intermediate (Vim) nucleus (cerebellar outflow). In addition to assessing on/off unilateral thalamic Vim stimulation on voice, the authors experimentally assessed low-voltage unilateral Vim, Voa, or multitarget stimulation in a prospective, randomized, doubled-blinded manner. The evaluators were experienced at rating SD and were familiar with the vocal tremor of ET. A Wilcoxon signed-rank test was used to study the pre- and posttreatment effect of DBS on voice. Unilateral left thalamic Vim stimulation (DBS on) significantly improved SD vocal dysfunction compared with no stimulation (DBS off), as measured by the USDRS (p < 0.01) and VRQOL (p < 0.01). In the experimental interrogation, both low-voltage Vim (p < 0.01) and multitarget Vim + Voa (p < 0.01) stimulation were significantly superior to low-voltage Voa stimulation. For the first time, the effects of high-frequency stimulation of different neural circuits in SD have been quantified. Unexpectedly, focused Voa (pallidal outflow) stimulation was inferior to Vim (cerebellar outflow) stimulation despite the classification of SD as a dystonia. While only a single case, scattered reports exist on the positive effects of thalamic DBS on dysphonia. A Phase 1 pilot trial (DEBUSSY; clinical trial no. NCT02558634, clinicaltrials.gov) is underway at the authors' center to evaluate the safety and preliminary efficacy of DBS in SD. The authors hope that this current report stimulates neurosurgeons to investigate this new indication for DBS.
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