PROMISE: Working with the CF community to understand emerging clinical and research needs for those treated with highly effective CFTR modulator therapy

Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis.     

Hip fracture mortality and morbidity in Switzerland and Japan: A cross-cultural comparison

Summary Based on national mortality data, the frequency of hip fractures in elderly people was compared between Switzerland and Japan. Age-adjusted annual incidence rates per 100 000 population estimated for Swiss persons over 60 years were around 150 and 200 in males and around 450 in females, while for the Japanese they were only 132 in males and 285 in females. Age-adjusted death rates from hip fracture for the Swiss over 60 were 20.0 in males and 28.9 in females, while for the Japanese they were only 1.6 in males and 2.7 in females. The inclination of the age-dependent slope in hip fracture mortality rates was substantially the same in both countries, but there was a lag time of approximately 10 years in Japan. Remarkably, the proportion of deaths due to falls among all accidental deaths was several times greater in both sexes for the Swiss than for the Japanese. This differential might be an important underlying reason for the observed difference between death rates of hip fracture in Switzerland and Japan. Other known behavioral risk factors for hip fracture such as diet, exercise, estrogen use etc. are unlikely to explain the observed difference in hip fracture mortality and morbidity between Switzerland and Japan. However, given the doubts on the reliability and thus comparability of the available data on mortality and morbidity, the present findings should be regarded as preliminary. In conclusion, we believe that the unexplained and large difference in the burden of hip fracture between Switzerland and Japan merits further studies, including new aetiological hypotheses.

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Zusammenfassung Gestützt auf nationale Sterbedaten wird die Häufigkeit von Hüftfrakturen bei Betagten in der Schweiz und Japan verglichen. Alterskorrigierte jährliche Inzidenzraten (bezogen auf 100 000 Einwohner) bezifferten sich bei den Schweizer Personen über 60 Jahren auf ca. 150–200 bei den Männern sowie ca. 450 bei den Frauen, während bei den Japanern die entsprechenden Inzidenzen lediglich 132 bei den Männern und 285 bei den Frauen betrugen. Die alterskorrigierte durch Hüftfrakturen bedinte Mortalität (pro 100000) betrug bei den Schweizern über 60 Jahren 20,0 bei den Männern und 28,9 bei den Frauen, während bei den Japanern die entsprechenden Werte bei 1,6 für Männer und 2,7 für Frauen lagen. Die Gerade, die das Verhältnis zwischen Alter und Hüftfraktur-Mortalität charakterisiert, zeigte in beiden Ländern ungefähr die gleiche Steigung, war in Japan jedoch um ca. 10 Jahre rechtsverschoben. Bemerkenswerterweise war der Anteil sturzbedingter Todesfälle unter allen unfallbedingten Todesfällen bei beiden Geschlechtern in der Schweiz wesentlich höher als in Japan. Dieser Unterschied könnte eine wichtige, zurgrundeliegende Ursache für die Differenz in der Hüftfrakturmortalität zwischen der Schweiz und Japan darstellen. Andere verhaltensabhängige Risikofaktoren für Hüftfraktur wie Ernährung, körperliche Bewegung, Oestrogenzufuhr usw. vermögen die beobachteten Unterschiede in der Mortalität und Morbidität an Hüftfraktur zwischen der Schweiz und Japan kaum zu erklären Angesichts der ungewissen Reliabilität und Vergleichbarkeit der zur Verfügung stehenden Daten müssen die vorliegenden Ergebnisse allerdings mit Vorsicht interpretiert werden. Zusammenfassend glauben wir, dass der grosse und weitgehend unerklärte schweizerisch-japanische Unterschied im Auftreten von Hüftfrakturen weiter abgeklärt werden sollte, unter Einschluss neuer ätiologischer Hypothesen.

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Résumé Basée sur les données de mortalité nationales, la fréquence des fractures de hanche des personnes âgées est comparée entre la Suisse et le Japon. Les taux d'incidence annuels corrigés pour l'effet de l'âge chez les personnes suisses âgées de plus de 60 ans sont d'environ 150–200 chez les hommes (par rapport à 100 000 habitants), ainsi qu'environ 450 chez les femmes, tandis qu'au Japon les incidences correspondantes s'élèvent à 132 chez les hommes et 285 chez les femmes. La mortalité des fractures de hanche, corrigée pour l'effet de l'âge s'élève chez les Suisses âgés de plus de 60 ans à 20,0 (par 100 000) chez les hommes et à 28,9 chez les femmes, alors que chez les Japonais les taux correspondants sont 1,6 chez les hommes et 2,7 chez les femmes. La proportion de décès faisant suite à des chutes parmi l'ensemble des accidents mortels est remarquablement plus élevée en Suisse qu'au Japon, pour les femmes comme pour les hommes. Cette différence pourrait expliquer le taux élvé de décès suite à une fracture de hanche observé en Suisse. D'autres facteurs de risque pour la fracture de hanche liés au style de vie ne sont apparemment pas en mesure d'expliquer les différences de mortalité et de morbidité par fracture de hanche observées entre la Suisse et le Japon. Face aux doutes qui concernent la fiabilité et la comparabilité des données à disposition, ces résultats doivent être interprétés avec prudence. Toutefois, nous pensons que la différence substantielle des taux de fractures de hanche entre Suisse et Japon, qui reste inexpliquée, devrait être examinée plus en détail, également en ce qui concerne de nouvelles hypothèses étiologiques.

     

Incidence of deep venous thrombosis after gynaecological laparoscopy

目的　研究妇科腹腔镜术后深静脉血栓的发生率。方法　在澳大利亚悉尼Liverpool医院 1997年 5月～ 1997年 9月 72例妇科腹腔镜手术采用Doppler超声检查静脉血流的通畅性和血管腔内的回声团用以诊断深静脉血栓。 61例患者充气时间 <60分钟为小手术组 ,11例 >60分钟为大手术组。每例患者在术后 2 4小时内及术后 7天行两次超声Doppler检查 ,所有 72人均行术后 2 4小时内的超声Doppler检查 ,小手术组 61例中 4 0例、大手术组 11例中 9例行二次超声检查。 2 3例未行二次超声检查者均行电话随访。结果　在我们的研究中两组患者均未发现DVT。本文同时报道北京复兴医院一例腹腔镜下右卵巢巧克力囊肿剥除术、左卵巢及部分输卵管切除术患者术后并发DVT ,其诊断及治疗经过。结论　这项研究证实妇科腹腔镜手术DVT虽发生率极低 ,一旦发生需及时诊治 ,以免发生肺栓塞等致命并发症。     

The protein phosphatase inhibitor calyculin A mimics elicitor action in plant cells and induces rapid hyperphosphorylation of specific proteins as revealed by pulse labeling with [33P]phosphate

Suspension-cultured tomato cells react to microbial signals, so-called elicitors, with rapid alkalinization of the growth medium and increased biosynthesis of the stress hormone ethylene. These responses to elicitors can be blocked by staurosporine and K-252a, two specific inhibitors of protein kinases. Here we show that calyculin A, a potent inhibitor of protein phosphatases, mimics the action of elicitors and, at nanomolar concentrations, induces medium alkalinization as well as a strong increase in the activity of 1-aminocyclopropane-1-carboxylate synthase, the key enzyme of ethylene biosynthesis. Both responses were strongly inhibited by K-252a, and calyculin A induced both responses more rapidly than did a fungal elicitor, xylanase. For example, the lag phase for medium alkalinization was only 0.2-0.4 min for calyculin A, compared with 2 min for xylanase. To study changes in the dynamics of protein phosphorylation, cells were labeled with 30-sec pulses of [33P]orthophosphate. Calyculin A strongly increased phosphorylation of several polypeptide bands within 40 sec of treatment. The same phosphorylated bands also appeared in response to xylanase, but only after a lag phase of 2-3 min. These results show that the protein phosphatase inhibitor calyculin A leads to rapid hyperphosphorylation of specific proteins in cultured cells and indicate that elicitor action could be based on inhibition of a protein phosphatase as well as on activation of a protein kinase.     

Taking the pulse of the community

In recent years, the technology and methodology have been developed to help you identify, collect, analyze, and apply health status information about the community you serve. Called a population-based community health status assessment, this tool is not intended to help you identify "needs"--you probably already know what many of them are in your community. Rather, it allows you to develop precise indicators of the health status of the community in general as well as of specific subgroups with particular health problems and risk factors. The assessment is useful both for the data and insights it provides and for organizing, implementing, and evaluating community health improvement interventions. Seven steps for the successful design and implementation of a population-based community health status assessment follow.     

Desensitization of guanylyl cyclases in cultured human airway smooth-muscle cells

We previously showed that cultured human airway smooth-muscle cells (HASMC) contain soluble and particulate guanylyl cyclases (GCs). We studied the desensitization of soluble and particulate GCs in HASMC. Homologous desensitization of soluble GC occurred after incubation with S-nitroso-N-acetyl pencillamine (SNAP). SNAP-dependent desensitization was blocked by hemoglobin, a nitric oxide (NO) scavenger, suggesting that it was due to NO release. Cross-desensitization between SNAP and sodium nitroprusside (SNP) and the lack of thiol reduction after SNAP or SNP treatment suggested that thiol depletion was not involved. Assays for soluble GC activity and experiments using protein synthesis inhibitors suggested that SNAP-dependent desensitization was due to reduced soluble GC. Homologous desensitization of particulate GC occurred after pretreatment with atrial natriuretic peptide (ANP) accompanied by reduced particulate GC activity. Recovery required protein synthesis, suggesting that it was due to reduction in particulate GC. Homologous desensitization to either SNAP or ANP was not altered by phosphodiesterase (PDE) inhibitors, suggesting that increased PDE activity was not involved. Cross-desensitization experiments using SNAP and ANP and experiments using zaprinast to elevate cyclic guanosine monophosphate showed no evidence of heterologous desensitization. Our results suggest that pretreatment of HASMC with SNAP or ANP causes homologous, but not heterologous, desensitization of soluble and particulate GCs, respectively.     

Comparison of four magnetic resonance methods for mapping small temperature changes

Non-invasive detection of small temperature changes (< 1 degree C) is pivotal to the further advance of regional hyperthermia as a treatment modality for deep-seated tumours. Magnetic resonance (MR) thermography methods are considered to be a promising approach. Four methods exploiting temperature-dependent parameters were evaluated in phantom experiments. The investigated temperature indicators were spin-lattice relaxation time T1, diffusion coefficient D, shift of water proton resonance frequency (water PRF) and resonance frequency shift of the methoxy group of the praseodymium complex (Pr probe). The respective pulse sequences employed to detect temperature-dependent signal changes were the multiple readout single inversion recovery (T One by Multiple Read Out Pulses; TOMROP), the pulsed gradient spin echo (PGSE), the fast low-angle shot (FLASH) with phase difference reconstruction, and the classical chemical shift imaging (CSI). Applying these sequences, experiments were performed in two separate and consecutive steps. In the first step, calibration curves were recorded for all four methods. In the second step, applying these calibration data, maps of temperature changes were generated and verified. With the equal total acquisition time of approximately 4 min for all four methods, the uncertainties of temperature changes derived from the calibration curves were less than 1 degree C (Pr probe 0.11 degrees C, water PRF 0.22 degrees C, D 0.48 degrees C and T1 0.93 degrees C). The corresponding maps of temperature changes exhibited slightly higher errors but still in the range or less than 1 degree C (0.97 degrees C, 0.41 degrees C, 0.70 degrees C, 1.06 degrees C respectively). The calibration results indicate the Pr probe method to be most sensitive and accurate. However, this advantage could only be partially transferred to the thermographic maps because of the coarse 16 x 16 matrix of the classical CSI sequence. Therefore, at present the water PRF method appears to be most suitable for MR monitoring of small temperature changes during hyperthermia treatment.     

Uveal melanoma: correlation of histopathologic and radiologic findings by using thin-section MR imaging with a surface coil

PURPOSE: To evaluate whether the different signal intensities at magnetic resonance (MR) imaging of melanoma are associated with a higher content of melanin. MATERIALS AND METHODS: In a prospective study, MR imaging and ophthalmoscopic examination findings in 42 patients (19 women, 23 men; age range, 30-87 years) with uveal melanoma were compared with histopathologic examination findings obtained after enucleation. MR imaging was performed with 2-mm sections by using a 5-cm surface coil. T1- and T2-weighted images were obtained before and after contrast material administration. RESULTS: In 33 (79%) of the patients, there was homogeneous tumor pigmentation, whereas in nine (21%) patients, there was inhomogeneous bipartite tumor pigmentation. Compared with the histopathologic data, the results of qualitative evaluation were accurate in 29 (58%) of 50 and in 26 (53%) of 49 tumorous areas on T1- and T2-weighted images, respectively. Quantitative evaluation yielded better results, especially at T1-weighted imaging; an 86% correlation was found. Because of methodological reasons, only the superficial pigmentation of inhomogeneous tumors could be evaluated with ophthalmoscopy. CONCLUSION: Thin-section MR imaging of the eye enables an accurate prediction of melanomatous pigmentation with quantitative evaluation of plain T1-weighted images and is superior to ophthalmoscopy in cases of inhomogeneous pigmentation.     

Evaluation of polyurethane stent implantation for the treatment of complete obstruction of the nasolacrimal system: 8-month follow-up and complications

Dacryocystorhinostomy is still the standard procedure complete stenosis of the nasolacrimal duct. New methods try to preserve the natural lacrimal pathway. Song implanted in 1995 a nasolacrimal polyurethane stent through the nasolacrimal duct. The results and complications of this new method are described in this prospective study. METHODS: Thirty consecutive patients with complete obstruction of the nasolacrimal duct or lacrimal sac were included in the study. The stenosis was localized by dacryocystography. The ages ranged from 22 to 87 years (mean, 58.9 +/- 16 years). Dacryocystography was performed immediately, 4 weeks and 8 months after the procedure to verify the position and patency of the stent. RESULTS: Twenty-five short (35 mm) and 5 long (45 mm) stents were implanted. Twenty-four of 30 patients after 4 weeks and 9 of 10 patients after 8 months had reduced or no complaints. In 1 patient the stent was obstructed. Forceful irrigation with saline solution permitted recanalization. In 1 patient the stent had moved into the upper canaliculus. Because of irritation of the canaliculus it had to be pulled out after 2 months. CONCLUSION: The follow-up is still too short to recommend stent implantation as a real alternative to dacryocystorhinostomy. The main advantages are that the procedure is faster, no incision is necessary, and the local anesthesia is easier. The disadvantage is the need for X-ray examination.