Comparison of Heart Team vs Interventional Cardiologist Recommendations for the Treatment of Patients With Multivessel Coronary Artery Disease.

Importance: Although the heart team approach is recommended in revascularization guidelines, the frequency with which heart team decisions differ from those of the original treating interventional cardiologist is unknown. Objective: To examine the difference in decisions between the heart team and the original treating interventional cardiologist for the treatment of patients with multivessel coronary artery disease. Design, Setting, and Participants: In this cross-sectional study, 245 consecutive patients with multivessel coronary artery disease were recruited from 1 high-volume tertiary care referral center (185 patients were enrolled through a screening process, and 60 patients were retrospectively enrolled from the center's database). A total of 237 patients were included in the final virtual heart team analysis. Treatment decisions (which comprised coronary artery bypass grafting, percutaneous coronary intervention, and medication therapy) were made by the original treating interventional cardiologists between March 15, 2012, and October 20, 2014. These decisions were then compared with pooled-majority treatment decisions made by 8 blinded heart teams using structured online case presentations between October 1, 2017, and October 15, 2018. The randomized members of the heart teams comprised experts from 3 domains, with each team containing 1 noninvasive cardiologist, 1 interventional cardiologist, and 1 cardiovascular surgeon. Cases in which all 3 of the heart team members disagreed and cases in which procedural discordance occurred (eg, 2 members chose coronary artery bypass grafting and 1 member chose percutaneous coronary intervention) were discussed in a face-to-face heart team review in October 2018 to obtain pooled-majority decisions. Data were analyzed from May 6, 2019, to April 22, 2020. Main Outcomes and Measures: The Cohen κ coefficient between the treatment recommendation from the heart team and the treatment recommendation from the original treating interventional cardiologist. Results: Among 234 of 237 patients (98.7%) in the analysis for whom complete data were available, the mean (SD) age was 67.8 (10.9) years; 176 patients (75.2%) were male, and 191 patients (81.4%) had stenosis in 3 epicardial coronary vessels. A total of 71 differences (30.3%; 95% CI, 24.5%-36.7%) in treatment decisions between the heart team and the original treating interventional cardiologist occurred, with a Cohen κ of 0.478 (95% CI, 0.336-0.540; P = .006). The heart team decision was more frequently unanimous when it was concordant with the decision of the original treating interventional cardiologist (109 of 163 cases [66.9%]) compared with when it was discordant (28 of 71 cases [39.4%]; P < .001). When the heart team agreed with the original treatment decision, there was more agreement between the heart team interventional cardiologist and the original treating interventional cardiologist (138 of 163 cases [84.7%]) compared with when the heart team disagreed with the original treatment decision (14 of 71 cases [19.7%]); P < .001). Those with an original treatment of coronary artery bypass grafting, percutaneous coronary intervention, and medication therapy, 32 of 148 patients [22.3%], 32 of 71 patients [45.1%], and 6 of 15 patients [40.0%], respectively, received a different treatment recommendation from the heart team than the original treating interventional cardiologist; the difference across the 3 groups was statistically significant (P = .002). Conclusions and Relevance: The heart team's recommended treatment for patients with multivessel coronary artery disease differed from that of the original treating interventional cardiologist in up to 30% of cases. This subset of cases was associated with a lower frequency of unanimous decisions within the heart team and less concordance between the interventional cardiologists; discordance was more frequent when percutaneous coronary intervention or medication therapy were considered. Further research is needed to evaluate whether heart team decisions are associated with improvements in outcomes and, if so, how to identify patients for whom the heart team approach would be beneficial.

Examining Risk: A Systematic Review of Perioperative Cardiac Risk Prediction Indices.

OBJECTIVE: To conduct a systematic review of published cardiac risk indices relevant to patients undergoing noncardiac surgery and to provide clinically meaningful recommendations to physicians regarding the use of these indices. METHODS: A literature search of articles published from January 1, 1999, through December 28, 2018, was conducted in Ovid (MEDLINE), PubMed, Embase, CINAHL, and Web of Science. Publications describing models predicting risk of cardiac complications after noncardiac surgery were included and citation chaining was used to identify additional studies for inclusion. RESULTS: Eleven risk indices involving 2,910,297 adult patients were included in this analysis. Studies varied in size, population, quality, risk of bias, outcome event definitions, risk factors identified, index outputs, accuracy, and clinical usefulness. Studies considered 6 to 83 variables to develop their models. Among the identified models, the factors with the highest predictiveness for adverse cardiac outcomes included congestive heart failure, type of surgery, creatinine, diabetes, history of stroke or transient ischemic attack, and emergency surgery. Substantial data from the large studies also supports advancing age, American Society of Anesthesiology physical status classification, functional status, and hypertension as additional risks. CONCLUSION: The risk indices identified generally fell into two groups - those with higher accuracy for predicting a narrow range of cardiac outcomes and those with lower accuracy for predicting a broader range of cardiac outcomes. Using one index from each group may be the most clinically useful approach. Risk factors identified varied widely among studies. In addition to judicious use of predictive indices, reasoned clinical judgment remains indispensable in assessing perioperative cardiac risk.

Diabetic neuropathy.

The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.

Safety of Continuing Trastuzumab Despite Mild Cardiotoxicity: A Phase I Trial.

OBJECTIVES: This study sought to evaluate the safety of continuing trastuzumab in patients with human epidermal growth factor receptor-positive breast cancer who developed mild cardiotoxicity. BACKGROUND: Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Current standard of care is discontinuation of trastuzumab, which can lead to worse cancer outcomes. It is unknown whether it is safe to continue trastuzumab despite mild cardiotoxicity. METHODS: Patients were eligible for this phase I, prospective, single-arm trial if left ventricular ejection fraction (LVEF) was between 40% and the lower limit of normal or if it fell ≥15% from baseline. Participants were treated with angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers in a cardio-oncology clinic and were followed clinically and with serial echocardiograms for 1 year. The primary outcome was cardiac dose-limiting toxicity, defined as cardiovascular death, LVEF <40% together with any heart failure symptoms, or LVEF <35%. RESULTS: All 20 participants received ACE inhibitors and/or beta-blockers. A total of 18 participants (90%) received all planned trastuzumab doses. Two (10%) participants developed cardiac dose-limiting toxicity (heart failure with LVEF <40%). Their LVEF and heart failure symptoms improved to nearly normal following permanent trastuzumab discontinuation. There were no deaths. LVEF rose progressively from a mean of 49% at enrollment to 55% at 12 months (p < 0.001). CONCLUSIONS: It may be feasible to continue trastuzumab despite mild cardiotoxicity in the setting of a cardio-oncology clinic, where ACE inhibitors and beta-blockers are administered. Approximately 10% of patients may develop moderate to severe heart failure using this approach. (Safety of Continuing Chemotherapy in Overt Left Ventricular Dysfunction Using Antibodies to Human Epidermal Growth Factor Receptor-2 [SCHOLAR]; NCT02907021).

Survey Analysis of the Use, Effectiveness, and Patient-Reported Tolerability of Inhaled Oxygen Compared With Injectable Sumatriptan for the Acute Treatment of Cluster Headache.

OBJECTIVE: In this secondary analysis of the Clusterbusters® Medication Use survey, the use, effectiveness, and tolerability of inhaled oxygen were investigated and compared with injectable sumatriptan. We also sought to understand the predictors of medication response. BACKGROUND: Inhaled oxygen is a mainstay abortive intervention in cluster headache but is not approved by the Food and Drug Administration (FDA). Unlike injectable sumatriptan, the only FDA-approved pharmacologic intervention for cluster headache, oxygen can be used multiple times a day, which is highly relevant for a condition with numerous daily attacks. In addition to obstacles in obtaining oxygen therapy, optimal oxygen delivery (ie, mask, flow rate) is not uniformly employed in cluster headache. These factors lead to underuse and imprecise therapeutic response rates. METHODS: A secondary analysis was conducted using deidentified data from the Clusterbusters® Medication Use survey, which was modeled after previously published surveys and available online. Subjects were recruited from headache clinics and cluster headache websites. Most responses were chosen from a list; others were free-texted. The final analysis included responses from 493 adult participants with a validated diagnosis of cluster headache. This analysis of deidentified data from the Clusterbusters® Medication Use survey received institutional approval. RESULTS: The most commonly used delivery system used by subjects was a non-rebreather-type mask. The use of oxygen flow rates >10 L/min was a positive predictor of medication response (OR = 2.36, P = .016). Among those who used flow rates >10 L/min, both inhaled oxygen (81.5%) and injectable sumatriptan (80.5%) were efficacious and did not differ significantly from each other in any specific group examined. At flow rates >10 L/min, positive predictors of oxygen response were male gender (OR = 2.07, P = .031) and cigarette smoking (current or historical; OR = 2.25, P = .017). Among the groups examined, there were no predictors of sumatriptan response. Most comments about side effects and concerns were directed at triptans. CONCLUSION: Therapeutic response to inhaled oxygen at sufficiently high flow rates (>10 L/min) had comparable efficacy to that of injectable sumatriptan for the acute treatment of cluster headache. Other factors in oxygen delivery (ie, flow rate changes) should be explored for optimization of therapy. The reasons for improved oxygen response in males and those with a cigarette smoking history require further exploration. While both oxygen and sumatriptan can be effective in the management of cluster headache, patient-reported side effects and concerns were more commonly directed at triptan medications. Current restrictions on access to inhaled oxygen, which exist at many levels, limit the therapeutic options available for patients with cluster headache, thereby doing a disservice to this patient population and the providers who deliver their care.

Analysis of Daily Laboratory Orders at a Large Urban Academic Center: A Multifaceted Approach to Changing Test Ordering Patterns.

OBJECTIVES: We sought to address concerns regarding recurring inpatient laboratory test order practices (daily laboratory tests) through a multifaceted approach to changing ordering patterns. METHODS: We engaged in an interdepartmental collaboration to foster mindful test ordering through clinical policy creation, electronic clinical decision support, and continuous auditing and feedback. RESULTS: Annualized daily order volumes decreased from approximately 25,000 to 10,000 during a 33-month postintervention review. This represented a significant change from preintervention order volumes (95% confidence interval, 0.61-0.64; P < 10-16). Total inpatient test volumes were not affected. CONCLUSIONS: Durable changes to inpatient order practices can be achieved through a collaborative approach to utilization management that includes shared responsibility for establishing clinical guidelines and electronic decision support. Our experience suggests auditing and continued feedback are additional crucial components to changing ordering behavior. Curtailing daily orders alone may not be a sufficient strategy to reduce in-laboratory costs.

Less is More in Diabetic Neuropathy Diagnosis: Comparison of Quantitative Sudomotor Axon Reflex and Skin Biopsy.

OBJECTIVES: To compare the frequency of abnormalities in epidermal nerve fiber density (ENFD) and quantitative sudomotor axon reflex (QSART) in patients with diabetic distal symmetric polyneuropathy (DSPN). METHODS: Nerve conduction studies, ENFD, and QSART data were obtained pre- and postexercise, in patients enrolled in a prospective diabetic neuropathy study. McNemar's test was applied to compare the yield of ENFD and QSART. RESULTS: Eighteen patients (58 ± 4 years) were enrolled, with 36 data collection points. In diabetic DSPN and diabetic large fiber DSPN (DSPN-L), abnormal ENFD (77% and 100% respectively) is more frequent than abnormal QSART (39% and 35%, respectively) (P value = 0.001 in diabetic DSPN and P value = 0.0002 in diabetic DSPN-L), whereas in diabetic small fiber DSPN (DSPN-S), both tests have similar yields (47%). CONCLUSIONS: ENFD has a high diagnostic yield in diabetic DSPN and DSPN-L. Including QSART data adds little to the sensitivity of EFND in DSPN-S.

An Educational and Administrative Intervention to Promote Rational Laboratory Test Ordering on an Academic General Medicine Service.

BACKGROUND: Overuse of clinical laboratory testing in the inpatient setting is a common problem. The objective of this project was to develop an inexpensive and easily implemented intervention to promote rational laboratory use without compromising resident education or patient care. METHODS: The study comprised of a cluster-randomized, controlled trial to assess the impact of a multifaceted intervention of education, guideline development, elimination of recurring laboratory orders, unbundling of laboratory panels, and redesign of the daily progress note on laboratory test ordering. The population included all patients hospitalized "general medicine" was duplicated during 2 consecutive months on a general medicine teaching service within a 999-bed tertiary care hospital in Boston, Massachusetts. The primary outcome was the total number of commonly used laboratory tests per patient day during 2 months in 2008. Secondary outcomes included a subgroup analysis of each individual test per patient day, adverse events, and resident and nursing satisfaction. RESULTS: A total of 5392 patient days were captured. The intervention produced a 9% decrease in aggregate laboratory use (rate ratio, 0.91; P = .021; 95% confidence interval, 0.84-0.98). Six instances of delayed diagnosis of acute kidney injury and 11 near misses were reported in the intervention arm. CONCLUSIONS: A bundled educational and administrative intervention promoting rational ordering of laboratory tests on a single academic general medicine service led to a modest but significant decrease in laboratory use. To our knowledge, this was the first study to examine the daily progress note as a tool to limit excessive test ordering. Unadjudicated near misses and possible harm were reported with this intervention. This finding warrants further study.

Thermal and pH Sensitive Multifunctional Polymer Nanoparticles for Cancer Imaging and Therapy.

In this study, we prepared novel poly(Glycerol malate co-dodecanedioate) (PGMD) NPs containing an imaging/hyperthermia agent (IR820) and a chemotherapeutic agent (doxorubicin, DOX). The PGMD polymer was prepared by thermal condensation. IR820 and DOX loaded PGMD NPs were prepared using the single oil emulsion technique. The size of the NPs measured was around 150 nm. Drug loading efficiency of DOX and IR820 was around 4% and 8%, respectively. An acidic environment (pH=5.0) induced higher DOX release as compared to pH=7.4. DOX release was also enhanced by exposure to laser, which increased the temperature to 42°C. Cytotoxicity of the drug loaded NPs was comparable in MES-SA but was higher in Dx5 cells compared to free drug (p<0.05). The combination of hyperthermia and chemotherapy improved cytotoxicity in both cell lines. The NP formulation significantly improved the plasma half-life of IR820 in mice after tail vein injection.

Peripheral nervous system insulin resistance in ob/ob mice.

BACKGROUND: A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. RESULTS: The results indicate that insulin signaling abnormalities documented in other "insulin sensitive" tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons. CONCLUSIONS: These findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy.

In vivo peripheral nervous system insulin signaling.

Alterations in peripheral nervous system (PNS) insulin support may contribute to diabetic neuropathy (DN); yet, PNS insulin signaling is not fully defined. Here, we investigated in vivo insulin signaling in the PNS and compared the insulin responsiveness to that of muscle, liver, and adipose. Non-diabetic mice were administered increasing doses of insulin to define a dose-response relationship between insulin and Akt activation in the dorsal root ganglion (DRG) and sciatic nerve. Resulting EC50 doses were used to characterize the PNS insulin signaling time course and make comparisons between insulin signaling in the PNS and other peripheral tissues (i.e., muscle, liver, and adipose). The results demonstrate that the PNS is responsive to insulin and that differences in insulin signaling pathway activation exist between PNS compartments. At a therapeutically relevant dose, Akt was activated in the muscle, liver, and adipose at 30 min, correlating with the changes in blood glucose levels. Interestingly, the sciatic nerve showed a similar signaling profile as insulin-sensitive tissues; however, there was not a comparable activation in the DRG or spinal cord. These results present new evidence regarding PNS insulin signaling pathways in vivo and provide a baseline for studies investigating the contribution of disrupted PNS insulin signaling to DN pathogenesis.

The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy.

UNLABELLED: Although exercise can significantly reduce the prevalence and severity of diabetic complications, no studies have evaluated the impact of exercise on nerve function in people with diagnosed diabetic peripheral neuropathy (DPN). The purpose of this pilot study was to examine feasibility and effectiveness of a supervised, moderately intense aerobic and resistance exercise program in people with DPN. We hypothesized that the exercise intervention can improve neuropathic symptoms, nerve function, and cutaneous innervation. METHODS: A pre-test post-test design was used to assess change in outcome measures following participation in a 10-week aerobic and strengthening exercise program. Seventeen subjects with diagnosed DPN (8 males/9 females; age 58.4±5.98; duration of diabetes 12.4±12.2 years) completed the study. Outcome measures included pain measures (visual analog scale), Michigan Neuropathy Screening Instrument (MNSI) questionnaire of neuropathic symptoms, nerve function measures, and intraepidermal nerve fiber (IENF) density and branching in distal and proximal lower extremity skin biopsies. RESULTS: Significant reductions in pain (-18.1±35.5 mm on a 100 mm scale, P=.05), neuropathic symptoms (-1.24±1.8 on MNSI, P=.01), and increased intraepidermal nerve fiber branching (+0.11±0.15 branch nodes/fiber, P=.008) from a proximal skin biopsy were noted following the intervention. CONCLUSIONS: This is the first study to describe improvements in neuropathic and cutaneous nerve fiber branching following supervised exercise in people with diabetic peripheral neuropathy. These findings are particularly promising given the short duration of the intervention, but need to be validated by comparison with a control group in future studies.

Core competency review: aortic stenosis and noncardiac surgery.

Aortic stenosis (AS) poses a risk of adverse cardiac events for patients undergoing surgical procedures. Perioperative mortality for patients with severe AS is as high as 14%. This review examines the accuracy of the history and physical examination in detecting AS and, subsequently, in assessing severity. The utility of echocardiography is addressed, and the relevant pathophysiology of AS is summarized. We also summarize what is known about perioperative risk for patients with AS.

Acidic saline-induced primary and secondary mechanical hyperalgesia in mice.

UNLABELLED: Most of our knowledge about chronic musculoskeletal pain is based on cutaneous pain models. To test the hypothesis that animals develop chronic muscular hyperalgesia following intramuscular acidic saline injections, primary hyperalgesia within the gastrocnemius muscle was analyzed compared to secondary cutaneous hyperalgesia in the hind paw that develops following intramuscular acid saline injection. Two acidic saline (pH 4) injections were administrated into the gastrocnemius of female CF-1 mice. The results indicate that mice developed a robust hypersensitivity bilaterally in primary (gastrocnemius muscle) secondary (cutaneous hind paw) sites that lasted up to 2 weeks. In addition, primary hyperalgesia correlated well with levels of Fos expression. Fos expression patterns in the spinal cord were different for primary secondary site stimulation. Hind-paw palpation stimulated ipsilateral Fos expression in the superficial spinal laminae at L4/L5 levels, bilaterally in deep laminae at L2-L5 spinal levels. In contrast, gastrocnemius compression stimulated widespread Fos expression in all regions of the ipsilateral dorsal horn within L2-L6 spinal segments. These findings indicate that acidic saline injection induces primary hyperalgesia in muscle that the patterns of Fos expression in response to primary vs secondary stimulation are strikingly different. PERSPECTIVE: This study assesses primary site muscular pain, which is the main complaint of people with musculoskeletal conditions, and identifies spinal patterns activated by noxious mechanical stimuli to the gastrocnemius. This study demonstrates approaches to test nociception arising from muscle aids in our understanding of spinal processing of primary secondary site hyperalgesia.

Perioperative surveillance for adverse myocardial events.

Perioperative myocardial infarctions occur in 1 to 4% of unselected noncardiac surgical patients, and are associated with high mortality. Detection of these events can be challenging, because 'typical' symptoms of myocardial ischemia may not be present or may be masked in the perioperative period. Therefore, surveillance by means of intraoperative cardiac monitoring and postoperative serial electrocardiograms (ECGs) and troponins may be needed. Cardiac monitoring not infrequently detects ST-segment changes suggestive of ischemia during or shortly after surgery. To respond to these changes, the risk for coronary artery disease should be assessed before recommending additional interventions. For all vascular surgery patients, and for patients who have or are felt to be at risk for coronary artery disease, serial postoperative 12-lead ECGs and troponins should be considered. Among surgical patients not meeting these criteria, obtaining routine ECGs in the absence of signs or symptoms that suggest a cardiac event may be falsely reassuring and is not felt to be useful. The presence of elevated postoperative troponins predicts worsened prognosis, and argues for intensified risk factor modification. The need for noninvasive cardiac testing or cardiac catheterization should be made on an individual basis.

Understanding the relative influence of neighborhood, family, and youth on adolescent drug use.

In the United States, a variety of programs have been developed to prevent substance use among youth. These programs often target youth directly, and may also have components that address the relational influence of families, schools, and communities. We discuss clustering of youth marijuana use within and between households and neighborhoods. As often discussed in the literature, we consider analyzing "components of variance" in a hierarchical sample design with two or more levels. With a continuous outcome variable, the estimated relative size of variance components at each level can be interpreted as its relative "importance." We estimate variance components when the outcome is dichotomous, and find that for the use of marijuana in the past year, the role of the individual (individual adolescent vs. role of household vs. role of neighborhood) is quite prominent (79% of variation). A similar result is observed for the continuous scale variable of individual positive attitudes toward drug use (83%). For continuous constructs related to either household (parental monitoring) or neighborhood (neighborhood disorganization) the majority of variation still occurs at the individual level (67% and 51%, respectively), although they reveal significant percent variation (about 30%) at the corresponding family or neighborhood levels as well. We discuss the use of variance component methodology and the relevance for prevention programs.

Diabetes-induced chemogenic hypoalgesia is paralleled by attenuated stimulus-induced fos expression in the spinal cord of diabetic mice.

UNLABELLED: Chronic hyperglycemia in diabetes induces abnormal nerve pathologies, resulting in diabetic neuropathy (DN). Sensory symptoms of DN can manifest as positive (painful), negative (insensate), or both. Streptozotocin (STZ)-induced diabetic C57Bl/6 mice have reduced cutaneous innervation and display reduced behavioral responses to noxious stimuli, reflecting the insensate aspect of the human syndrome. Current studies were undertaken to determine whether the diabetes-induced deficits in pain responses are reflected by changes in spinal activation in this model of DN. Nocifensive responses of nondiabetic and diabetic mice to formalin injection were measured 1, 3, 5, and 7 weeks after STZ, and at each time point formalin-induced spinal Fos expression was quantified. Responses of diabetic mice were significantly reduced during the second phase of the formalin test beginning 3 weeks after STZ and during Phase 1 beginning 5 weeks after STZ. Consistent with the behavioral responses, the number of Fos-positive cells in the dorsal horn of diabetic animals was significantly reduced beginning 3 weeks after STZ and continuing 5 and 7 weeks after STZ. The deficits at 5 weeks after STZ were restored by 2-week treatments with insulin or neurotrophins. These results demonstrate that the reduced sensation occurring from progressive peripheral axon loss results in functional deficits in spinal cord activation. PERSPECTIVE: The reduced expression of the immediate early gene Fos as an indicator of pain transmission supports the diabetes-induced loss of sensation in this Type 1 model of diabetes. This murine model may be better suited to understanding the insensate symptoms of diabetic patients in the absence of chronic pain.