Are frequent callers to family physicians high utilizers?

PURPOSE: Our objective was to describe patients who telephone frequently after hours to physicians (frequent callers) and categorize their medical problems and resource utilization. METHODS: Charts of frequent callers were reviewed and compared with those of a systematically selected group from the same family medicine residency practice (control group). Data collected included demographic and clinical information, as well as information on utilization of office, emergency department, and hospital services. In addition, 4 family physicians reviewed the patient information and identified the primary diagnosis for frequent callers. RESULTS: Frequent callers were predominately female; had 3 times as many office visits, diagnoses, and medications; and had 8 times as many hospital admissions as the control group. The most common primary diagnostic categories were psychiatric disorders (36%), pain (21%), chronic illnesses (16%), pregnancy (13%), and common problems of childhood (9%). CONCLUSIONS: Frequent callers represent a unique group of patients with high utilization of health care services. Better targeted patient education and referral to other support services may decrease the number of calls and utilization of health services. Alternatively, among high utilizers, frequent telephone calls may be a substitute for other forms of care.     

Assessing the Causal Role of Sleep Traits on Glycated Hemoglobin: A Mendelian Randomization Study

OBJECTIVETo examine the effects of sleep traits on glycated hemoglobin (HbA_1c).RESEARCH DESIGN AND METHODSThis study triangulated evidence across multivariable regression (MVR) and one- (1SMR) and two-sample Mendelian randomization (2SMR) including sensitivity analyses on the effects of five self-reported sleep traits (i.e., insomnia symptoms [difficulty initiating or maintaining sleep], sleep duration, daytime sleepiness, napping, and chronotype) on HbA_1c (in SD units) in adults of European ancestry from the UK Biobank (for MVR and 1SMR analyses) (n = 336,999; mean [SD] age 57 [8] years; 54% female) and in the genome-wide association studies from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) (for 2SMR analysis) (n = 46,368; 53 [11] years; 52% female).RESULTSAcross MVR, 1SMR, 2SMR, and their sensitivity analyses, we found a higher frequency of insomnia symptoms (usually vs. sometimes or rarely/never) was associated with higher HbA_1c (MVR 0.05 SD units [95% CI 0.04–0.06]; 1SMR 0.52 [0.42–0.63]; 2SMR 0.24 [0.11–0.36]). Associations remained, but point estimates were somewhat attenuated after excluding participants with diabetes. For other sleep traits, there was less consistency across methods, with some but not all providing evidence of an effect.CONCLUSIONSOur results suggest that frequent insomnia symptoms cause higher HbA_1c levels and, by implication, that insomnia has a causal role in type 2 diabetes. These findings could have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycemia and prevent diabetes.     

A role for nitroxyl (HNO) as an endothelium-derived relaxing and hyperpolarizing factor in resistance arteries

Background and purpose:

Nitroxyl (HNO) is emerging as an important regulator of vascular tone as it is potentially produced endogenously and dilates conduit and resistance arteries. This study investigates the contribution of endogenous HNO to endothelium-dependent relaxation and hyperpolarization in resistance arteries.

Experimental approach:

Rat and mouse mesenteric arteries were mounted in small vessel myographs for isometric force and smooth muscle membrane potential recording.

Key results:

Vasorelaxation to the HNO donor, Angeli''s salt, was attenuated in both species by the soluble guanylate cyclase inhibitor (ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one), the voltage-dependent K⁺ channel inhibitor, 4-aminopyridine (4-AP) and the HNO scavenger, l-cysteine. In mouse mesenteric arteries, nitric oxide (NO) synthase inhibition (with l-NAME, N^ω-Nitro-L-arginine methyl ester) markedly attenuated acetylcholine (ACh)-mediated relaxation. Scavenging the uncharged form of NO (NO^•) with hydroxocobalamin (HXC) or HNO with l-cysteine, or 4-AP decreased the sensitivity to ACh, and a combination of HXC and l-cysteine reduced ACh-mediated relaxation, as did l-NAME alone. ACh-induced hyperpolarizations were significantly attenuated by 4-AP alone and in combination with l-NAME. In rat mesenteric arteries, blocking the effects of endothelium-derived hyperpolarizing factor (EDHF) (charybdotoxin and apamin) decreased ACh-mediated relaxation 10-fold and unmasked a NO-dependent component, mediated equally by HNO and NO^•, as HXC and l-cysteine in combination now abolished vasorelaxation to ACh. Furthermore, ACh-evoked hyperpolarizations, resistant to EDHF inhibition, were virtually abolished by 4-AP.

Conclusions and implications:

The factors contributing to vasorelaxation in mouse and rat mesenteric arteries are NO^• = HNO > EDHF and EDHF > HNO = NO^• respectively. This study identified HNO as an endothelium-derived relaxing and hyperpolarizing factor in resistance vessels.British Journal of Pharmacology (2009) 157, 540–550; doi:10.1111/j.1476-5381.2009.00150.x; published online 26 March 2009This article is commented on by Martin, pp. 537–539 of this issue and is part of a themed section on Endothelium in Pharmacology. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009     

Natural and synthetic flavonoid modulation of TRPC5 channels

Background and Purpose

The TRPC5 proteins assemble to create calcium‐permeable, non‐selective, cationic channels. We sought novel modulators of these channels through studies of natural products.

Experimental Approach

Intracellular calcium measurements and patch clamp recordings were made from cell lines. Compounds were generated by synthetic chemistry.

Key Results

Through a screen of natural products used in traditional Chinese medicines, the flavonol galangin was identified as an inhibitor of lanthanide‐evoked calcium entry in TRPC5 overexpressing HEK 293 cells (IC₅₀ 0.45 μM). Galangin also inhibited lanthanide‐evoked TRPC5‐mediated current in whole‐cell and outside‐out patch recordings. In differentiated 3T3‐L1 cells, it inhibited constitutive and lanthanide‐evoked calcium entry through endogenous TRPC5‐containing channels. The related natural flavonols, kaempferol and quercetin were less potent inhibitors of TRPC5. Myricetin and luteolin lacked effect, and apigenin was a stimulator. Based on structure–activity relationship studies with natural and synthetic flavonols, we designed 3,5,7‐trihydroxy‐2‐(2‐bromophenyl)‐4H‐chromen‐4‐one (AM12), which inhibited lanthanide‐evoked TRPC5 activity with an IC₅₀ of 0.28 μM. AM12 also inhibited TRPC5 activity evoked by the agonist (−)‐Englerin A and was effective in excised outside‐out membrane patches, suggesting a relatively direct effect. It inhibited TRPC4 channels similarly, but its inhibitory effect on TRPC1–TRPC5 heteromeric channels was weaker.

Conclusions and Implications

The data suggest that galangin (a natural product from the ginger family) is a TRPC5 inhibitor and that other natural and synthetic flavonoids contain antagonist or agonist capabilities at TRPC5 and closely related channels depending on the substitution patterns of both the chromone core and the phenyl ring.

Abbreviations

LPC

lysophosphatidylcholine

S1P

sphingosine 1‐phosphate

     

Coronavirus Disease Contact Tracing Outcomes and Cost,Salt Lake County,Utah, USA,March–May 2020

Outcomes and costs of coronavirus disease (COVID-19) contact tracing are limited. During March–May 2020, we constructed transmission chains from 184 index cases and 1,499 contacts in Salt Lake County, Utah, USA, to assess outcomes and estimate staff time and salaries. We estimated 1,102 staff hours and $29,234 spent investigating index cases and contacts. Among contacts, 374 (25%) had COVID-19; secondary case detection rate was ≈31% among first-generation contacts, ≈16% among second- and third-generation contacts, and ≈12% among fourth-, fifth-, and sixth-generation contacts. At initial interview, 51% (187/370) of contacts were COVID-19–positive; 35% (98/277) became positive during 14-day quarantine. Median time from symptom onset to investigation was 7 days for index cases and 4 days for first-generation contacts. Contact tracing reduced the number of cases between contact generations and time between symptom onset and investigation but required substantial resources. Our findings can help jurisdictions allocate resources for contact tracing.     

Liver transplantation and waitlist mortality for HCC and non‐HCC candidates following the 2015 HCC exception policy change

Historically, exception points for hepatocellular carcinoma (HCC) led to higher transplant rates and lower waitlist mortality for HCC candidates compared to non‐HCC candidates. As of October 2015, HCC candidates must wait 6 months after initial application to obtain exception points; the impact of this policy remains unstudied. Using 2013‐2017 SRTR data, we identified 39  350 adult, first‐time, active waitlist candidates and compared deceased donor liver transplant (DDLT) rates and waitlist mortality/dropout for HCC versus non‐HCC candidates before (October 8, 2013‐October 7, 2015, prepolicy) and after (October 8, 2015‐October 7, 2017, postpolicy) the policy change using Cox and competing risks regression, respectively. Compared to non‐HCC candidates with the same calculated MELD, HCC candidates had a 3.6‐fold higher rate of DDLT prepolicy (aHR = _3.49 3.69 _3.89) and a 2.2‐fold higher rate of DDLT postpolicy (aHR = _2.09 2.21 _2.34). Compared to non‐HCC candidates with the same allocation priority, HCC candidates had a 37% lower risk of waitlist mortality/dropout prepolicy (asHR = _0.54 0.63 _0.73) and a comparable risk of mortality/dropout postpolicy (asHR = _0.81 0.95 _1.11). Following the policy change, the DDLT advantage for HCC candidates remained, albeit dramatically attenuated, without any substantial increase in waitlist mortality/dropout. In the context of sickest‐first liver allocation, the revised policy seems to have established allocation equity for HCC and non‐HCC candidates.     

A new Ig-superfamily member,molluscan defence molecule (MDM) from Lymnaea stagnalis,is down-regulated during parasitosis

To survive the attacks of the internal defence system (IDS) of their host, parasites have developed various strategies to manipulate the IDS. We present evidence that the avian schistosome parasite Trichobilharzia ocellata affects gene expression in the granular cells, a cell type of the IDS of the intermediate host, the mollusc Lymnaea stagnalis. From a differential screening, a clone was isolated encoding a protein named molluscan defence molecule (MDM), which encompasses five C2-like immunoglobulin (Ig) domains. The protein shares a domain organization and high amino acid sequence identity with hemolin, an Ig-family member of the insect IDS. Interestingly, both MDM and hemolin have highest sequence identity with neural cell adhesion molecules, but lack the typical fibronectin repeats and motifs for membrane anchors. We find that the expression of the MDM gene is gradually down-regulated during the course of parasitosis to ～21% compared to the non-parasitized level, 8 weeks post-infection. Based on our findings, we suggest that MDM is involved in the proper functioning of the Lymnaea IDS, and that down-regulation of MDM is part of the parasite-induced disabling of non-self recognition.