text:
ROHE METHOD
HEARING CONDITIONS
MUSICIANS CLINIC
Desyncra
Misophonia
Starkey Livio AI
Hearing Aid Cost
Contact / Forms
Oticon OpenSound Navigator (OSN) and Multi-Speaker Access Technology (MSAT)
In 2016, Oticon Medical introduced its Opn™ hearing aid, which offers Multi-Speaker Access Technology (MSAT) in Oticon's OpenSound Navigator™ (OSN).
Oticon OpenSound Navigator (OSN)
The Open Sound Navigator (OSN) is a technology that removes excessive background noise in a split second so you can focus on what's important. It also assists you to locate the exact direction from where the sound is coming.
OSN is a noise reduction algorithm consisting of three modules - Analyze, Balance, and Noise Removal. These three together identifies the direction of the exact speech, sharpens it and then amplifies it.
Multi-Speaker Access Technology (MSAT)
MSAT technology is a BrainHearing™ technology. BrainHearing™ technology is a feature that emulates the way your brain normally processes a sound.
To understand further, imagine a normal hearing person, trying to listen to Julie talking about her vacation, in a busy restaurant. The brain would quickly work in four stages. Firstly, it will orient itself to the noisy place; secondly, it would distinguish Julie's voice from the rest. Thirdly, the brain would focus on the exact words spoken, and finally, it will rebalance the sounds and help distinguish every word clearly.
Speech in Noise (SIN)
If you suffer from hearing loss and even though you use a hearing aid, you may find it frustrating to understand speech in noise (SIN). If you tried to listen to Julie in that busy restaurant, it would probably be difficult to be able to distinguish Julie's speech from others talking in the room. Most hearing aids cannot effectively filter the speech in noise.
The new Oticon hearing aids with BrainHearing™ technology help to mimic exactly what the brain normally does, which means it can extract the speech in noise.
MSAT technology is an extraordinary application used in hearing aids. It selectively reduces disturbing noises while maintaining access to all distinct speech sounds. It does not isolate one voice, instead maintains access to all distinct speakers. It frees the capacity of the brain to store and recall information.
Advantages of OSN and MSAT technology
1. Efficient
Listening is where hearing meets the brain. Listening effort is higher in a noisy environment. More cognitive processes need to be engaged in a noisy environment in order to recognize speech. To be able to actually ignore the surrounding noise, and understand the meaning of the words spoken, is not that easy!
Comparison of the 'giving –up' recent study observed the listening effort of two groups of people, one with OSN and the other with a non-OSN hearing aid. These two groups were compared with the normal hearing group in the study.
They used a method called pupillometry that measured pupil dilation as a reaction to stress.
The idea was, to see at what point do people 'give up' trying to listen. Giving up happens if the task becomes too difficult and the benefit does not outweigh the listening effort required.
Using Open Sound Navigator (OSN) is as good as normal. Normal-hearing listeners were able to focus till -4 dB SNR (signal to noise ratio) after which they started giving up. The OSN group had a very similar experience but the non-OSN group gave up much sooner.
Further research like the SWIR Test (Sentence-Final Word Identification and Recall) and speech recognition showed that the OSN algorithm significantly improves memory for speech heard in noise and better speech understanding in noise.
The processing speed of the new BrainHearing™ technology is 50 times faster than the previous generation of essential hearing aids. It delivers high-resolution sound quality to improve speech understanding.
All these data support the fact that OSN technology is efficient.
2. Useful if you have tinnitus
A study by Jensen in 2018 reported that OSN significantly reduced listening effort for people with tinnitus. Usually, when the pupil dilation test is carried out in people with tinnitus, they display severe stress and fatigue. With OSN, their stress level reduced and they needed less effort to listen.
3. High user satisfaction
Based on feedback to questionnaires distributed to regular OSN users, user satisfaction is high. The ON app that comes with the hearing aid, make it very easy to use. It allows them to expend less effort, have better recall, and better speech understanding in noisy environments.
This technology empowers the user to actively participate in social situations in the same way as their normal-hearing peers.
4. User-friendly
As already mentioned, the ON App makes the Oticon hearing aids very user-friendly. Besides the OSN, MSAT and BrainHearing™ features, there is another additional feature called HearingFitness™ that optimizes the hearing health behavior. It monitors the duration of wearing the hearing aid and prompts you to reach your goals. It also tracks the noise levels of places you frequently visit.
There are many easy to use features that make it very attractive. It is small in size and comes in a variety of styles that you can choose from. It also has a long battery life and can be connected online, with Bluetooth. These features are useful if you are traveling or if you want to check your user behavior.
5. Recommended for first-time users
According to Oticon Medical, this range of hearing aids is the "smallest hearing aid style Oticon has ever produced," making it very attractive to first-time users.
Clinicians can encourage people using the Opn™ hearing aids to explore listening and social situations they may have avoided or given up on in the past. HearingFitness is another feature that would attract the first time user.
Beck DL, Le Goff N. A Paradigm Shift in Hearing Aid Technology. Hearing Review. 2016;23(6):18-20.
Le Goff N, Jensen J, Pedersen MS, Callaway SL. An Introduction to OpenSound Navigator™.
Sockalingam R, Beilin J, Beck DL. Sound quality considerations of hearing instruments. Hearing Review. 2009; 16(3):22-28.
Jensen J, Callaway SL, Lunner T, Wendt D. Measuring the Impact of Tinnitus on Aided Listening Effort Using Pupillary Response.Trends in Hearing. 2018;22: 1–17
Kochkin S. MarkeTrak VII: Customer satisfaction with hearing instruments in the digital age. Hear Jour. 2005; 58(9):30-37.
Abrams, HB. Kihm, J. (2015): Abrams HB, Kihm J. An Introduction to MarkeTrak IX: A New Baseline for the Hearing Aid Market. Hearing Review. 2015;22(6):16-21.
The Oticon technologies and diligent research continue to impress us at Tinnitus & Hearing Center of Arizona, and it's one of our leading hearing aid brands that we recommend, fit, and service. We currently offer a 30-day free trial of Oticon hearing aids and other brands, so if you think these could be a good fit for you or your loved one, we encourage you to contact our office at (480) 831-6159.
Newest Hearing Aid Technology Breaks the Rules to Deliver Speech Understanding on Par with Normal Hearing
In hearing care, there are some rules you never break. For Allen and Amy Rohe of Tinnitus and Hearing Center of Arizona in Tempe, face-to-face consultations, professionally administered hearing checks and follow-up care that ensures patient satisfaction are the foundation of their success in caring for Phoenix metro residents. Staying attuned to breakthrough hearing technologies that will benefit new and existing patients is also central to their approach to quality hearing healthcare.
Tinnitus and Hearing Center of Arizona is among the first US hearing care professionals to offer Oticon Opn S™, a groundbreaking new hearing aid that allows people with hearing loss to experience speech understanding in difficult listening situations, such as restaurants or social gatherings, at the level of people with normal hearing.*
"Opn S hearing aids push the boundaries of what you can expect from a hearing aid to make a tremendous difference in how you hear and participate in life," explains Dr. Rohe. "Ultra-fast sound processing opens up a rich, 360-degree world of sound so you can follow conversations in a group of people and focus on what's important to you, even in noisy environments. And when you need extra help in especially noisy situations, Opn S lets you 'boost' the support you receive – whenever you feel you need it."
This small, discreet hearing aid features Oticon's exclusive BrainHearing™ technology to provide unprecedented access to the details of speech that helps the brain make sense of sound. People won't have to work as hard to hear, so they'll feel less stress and will be more likely to join in conversations.
"Staying connected is increasingly important today," says Amy Rohe. "Opn S connects wirelessly to iPhone® so you can stream audio or music right to your hearing aids. A TV Adapter lets you turn your hearing aids into wireless headphones so you can enjoy TV with family and friends at a volume that's comfortable for everyone."
Tinnitus and Hearing Center of Arizona points out that people who want the convenience of rechargeable batteries can choose Opn S, which offers a state-of-the-art rechargeable lithium-ion solution. An easy overnight charge provides a full-day of listening power.**
Dr. Rohe is a nationally-recognized audiologist specializing in Tinnitus Therapy and other hearing conditions.
Hearing Ability
Hearing Damage
Hyperacusis Treatment
Misophonia Treatment
Notch Therapy
Online Treatment
Tinnitus Causes
Tinnitus and Hearing Center of Arizona
2034 E. Southern Avenue, Suite I, Tempe, AZ 85282
Find us on the Web
Areas We've Served
We serve patients locally at our Tempe, AZ area clinic, as well as remotely via internet chat in certain cases. Below are just some of the areas our patients live with better hearing!
Phoenix AZ, Scottsdale, Chandler, Gilbert, Mesa, Sun City, Peoria, Queen Creek, Cave Creek, Green Valley, Buckeye, Gold Canyon, San Tan Valley, Maricopa, Surprise, Cottonwood, Overgaard, Laveen, Pinetop, Anthem, Sierra Vista, Kearny, Paradise Valley, Goodyear, Glendale, Litchfield Park, Flagstaff, Sedona, Tucson, Lake Havasu City, Sun Lakes, Fountain Hills, Ahwatukee
Greater USA
Houston, TX; Denver, CO; Los Angeles, CA; Lubbock, TX; Dallas, TX; Beaumont, TX; Anchorage, AK; Weathersfield, CT; Corpus Christi, TX; Portland, OR; Marshall, AR; Albuquerque, NM; New York, NY; Amarillo, TX; Hobbs, NM; Washington, D.C.; San Diego, CA; San Jose, CA; Santa Rosa, CA; Las Vegas, NV; Roseville, CA; Woodstock, MD; Ketchikan, AK; Austin, TX; San Francisco, CA; McComb, MI; McHenry, IL; Chicago, IL; Springfield, IL
Sweden; Rio De Janeiro, Brazil; Israel; Kathmandu, Nepal; Toronto, Canada; Queensland, Australia
Site Design & SEO by Synergy Wellness Marketing


text:
Bulacan (provincie), een provincie in de Filipijnen;
 Bulacan (Bulacan), een gemeente in de Filipijnse provincie Bulacan.

redpajama_set_name: RedPajamaWikipedia


text:
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{
    using System;

    public interface IReader : IDisposable
    {
        long Length { get; }
        long Position { get; }
        void Seek(long position);
        int CountLines();
        string ReadLine();
    }
}

redpajama_set_name: RedPajamaGithub


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text:
package org.bitvector.microservice2;

import akka.actor.AbstractActor;
import akka.event.Logging;
import akka.event.LoggingAdapter;
import akka.japi.pf.ReceiveBuilder;
import io.undertow.Handlers;
import io.undertow.Undertow;
import io.undertow.UndertowOptions;
import io.undertow.server.RoutingHandler;
import org.apache.shiro.SecurityUtils;
import org.apache.shiro.mgt.DefaultSecurityManager;
import org.apache.shiro.realm.text.IniRealm;
import org.apache.shiro.session.mgt.DefaultSessionManager;
import org.apache.shiro.session.mgt.eis.EnterpriseCacheSessionDAO;

import java.io.Serializable;

public class HttpActor extends AbstractActor {
    private LoggingAdapter log = Logging.getLogger(getContext().system(), this);
    private SettingsImpl settings = Settings.get(getContext().system());
    private Undertow server;

    public HttpActor() {
        DefaultSecurityManager securityManager = new DefaultSecurityManager(new IniRealm("classpath:shiro.ini"));

        DefaultSessionManager sessionManager = new DefaultSessionManager();
        sessionManager.setSessionDAO(new EnterpriseCacheSessionDAO());
        sessionManager.setCacheManager(new HazelcastCacheManager());
        sessionManager.setSessionValidationSchedulerEnabled(false);

        securityManager.setSessionManager(sessionManager);
        SecurityUtils.setSecurityManager(securityManager);

        receive(ReceiveBuilder
                        .match(Start.class, this::doStart)
                        .match(Stop.class, this::doStop)
                        .matchAny(obj -> log.error("HttpActor received unknown message " + obj.toString()))
                        .build()
        );
    }

    private void doStart(Start msg) {
        log.info("HttpActor received start");

        ProductCtrl productCtrl = new ProductCtrl(getContext());

        RoutingHandler rootHandler = Handlers.routing()
                .addAll(productCtrl.getRoutingHandler());

        server = Undertow.builder()
                .addHttpListener(settings.LISTEN_PORT(), settings.LISTEN_ADDRESS(), rootHandler)
                .setServerOption(UndertowOptions.ENABLE_HTTP2, true)
                .build();

        try {
            server.start();
        } catch (RuntimeException e) {
            log.error("Failed to create HTTP actor: " + e.getMessage());
            getContext().stop(self());
        }
    }

    private void doStop(Stop msg) {
        log.info("HttpActor received stop");
        server.stop();
    }

    public static class Start implements Serializable {
    }

    public static class Stop implements Serializable {
    }
}


The interface between proliferation and differentiation is a key point of regulation in development. Among elements of the environment that influence these alternative states is a structurally related family of fourteen polypeptides (see references in Coulier et al., 1997), the fibroblast growth factors, half of which are expressed in the brain. These growth factors play crucial roles in both normal physiological (such as embryonic and postnatal development, nervous system differentiation, angiogenesis and wound repair) and pathological (such as tumorogenesis and metastasis) processes (reviewed in Basilico and Moscatelli, 1992; Eckenstein, 1994). The most extensively studied member of this family, FGF-2 (commonly known as basis fibroblast growth factor), targets a broad spectrum of cell types derived from mesoderm and neuroectoderm. It induces a variety of biological activities, such as the inhibition or stimulation of differentiation, proliferation, chemotaxis, enhanced survival and cytoskeletal alterations.


Will One of These Be Future Staff?
This week we have had 15 locals from across China come start a three-month stay at our farm. Unlike most Chinese, they did not come looking for ways to advance their careers or make more money. They are coming for training on how to serve others.
While we technically are just giving a location for their training, these next few months give us excellent exposure to a group of people who may want to stay and serve the vision of helping teenage orphan girls.
Building our team is the prime initiative for our staff at the farm. We need two more full-time staff before we invite more orphans to come to the farm.
This month some bad news about social organizations in China, who are helping foster orphans, came to the surface. The reports are 20 kids died within 49 days at one care center. I don't know the details of what happened, but the ramifications are that all foreign run care centers are being scrutinized.
Foreign friends of our organization, who have a care center in another province, had all of their kids removed from their care and sent back to the state-run orphanage. A second care center, which is near us, has been allowed to keep several special needs kids but has not been given as many as before.
Both care centers need to figure out what they will do with their local staff. The second one has asked if we had need for one of their staff couples.
We took a different approach entering into China. We created a local business so we could hire teenage orphan girls. As a business, we could provide a place to live for our employees, set up employee training to improve their work, and give a living wage to improve their self-worth.
As such, our work for teenage orphan girls is an overflow of improving the lives of our employees. Your support of us gives life to our girls, our staff, our clients, and so many more families and individuals. We are a business that seeks to do social good in China.
Can We Pay The Foster Care Couple?
The offer of the staff couple from our friends' care center can help us greatly. We will need to interview them and see if they even want to come to work for us. But if we keep to their current pay scale, we will need to raise $600 monthly to pay for them. Please let us know if you would like to provide for the hiring of these caregivers.
This year we started in on the third phase of Josiah's Covenant. It is such an exciting and yet kind of scary time. Our family moved back to the US trusting the in-country work to our Chinese staff. Handing off your work to locals is the goal of everyone who wants to see significant long-term success in another country. So this is a celebration.
Let us know if you would like a copy of the business plan, so you can see how things will move forward from here. It is more detailed than many of you will want to read, but take a glance and know your investment is going to help the lives of many orphan girls in the future.
In front of the plan is a one-page executive summary. If you don't have time to read the whole plan, at least take in that page. Your informed prayers and financial contributions are crucial to the success of Josiah's Covenant.
We have connected with many of you the last couple months. It has been great to catch up and to be updated in your life story. We'd love to hear from more of you. Each of you is a blessing to us. You can always reply to this email to share with us what is going on. We are grateful for your investment in Josiah's Covenant. Thank you!


text:
DAVID Y. THOMAS
VIPER, the lentiviral IPPER platform for drug discovery in trafficking diseases. IPPER-accelerated development of pharmacological correctors for cystic fibrosis
Friday January 7th, 2022
Challenge: Drug discovery by high-throughput screening of candidate compounds faces challenges and needs the development and validation of specific platforms. An example of complex diseases that would benefit from such platforms is cystic fibrosis, a lung disease caused by genetics and aggravated by air pollution. An immediate response of bronchial epithelial cells to pollution is the downregulation of CFTR from the cell surface. This initiates a cascade of degenerative processes leading to the disease of cystic fibrosis.
Solution: IPPER is a platform developed within a collaboration between McGill University and LDC (Germany) funded by CQDM through the Québec-Germany program to establish a series of novel techniques and reagents to detect new compounds with endoplasmic reticulum (ER)-stress modifying characteristics. This new project is an excellent opportunity to apply the developed IPPER platform to a complex problem, such as acquired cystic fibrosis, and to demonstrate its multiple use. The main goal of this project is to develop and validate the Viral Integrated platform for the Pharmacology of the ER (VIPER), the lentiviral and enhanced version of IPPER, and prove its utility for drug discovery in trafficking diseases. The platform will identify and verify potential therapeutic compounds and their mechanism of action by direct assessment in patient cells under recreated air pollution stress.
Achievements/Impact: Beside the major benefits associated with the discovery of new candidate drugs to treat acquired cystic fibrosis, an important achievement will be the availability of a new tool, a patient cell-based platform in the development of novel pharmaceuticals.
By benefitting from the multiple funders' contributions and by coordinating the individual expertise of several renowned institutes, the project will strengthen these international partnerships that productively tackle global challenges. This will increase the capabilities of Traffick Therapeutics, a Montréal-based R&D company that specializes in the development of molecules with therapeutic potential up to the pre-clinical phase, to attract new investments and further expand its development.
Graeme Carlile
Gregor Jansen
John Hanrahan
Traffick Therapeutics
Bert Klebl
Lead Discovery Center (Germany)
$3,071,147 / 3 years
Supported by CQDM through:
And by co-funding partners:
• Traffick Therapeutics
• Lead Discovery Center
• Cystic Fibrosis Canada
• CIHR

redpajama_set_name: RedPajamaCommonCrawl


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for the creation of custom moulded Digital Keys.
This has expanded the possibilities for corporate marketing, promotions and brand awareness.
it delivers a memorable and unique offering.
to suit your budget and lead time.
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A Digital Key that is specifically designed and manufactured in a shape that best demonstrates your brand, product or service. It delivers long term advertising opportunities. With its higher perceived value and widespread use, clients keep and re-use them. Because it is manufactured in a custom shape specific for you and you only, it will promote your company and repeatedly remind people of your product or service.


Friends of Scott received the San Diego Padres Second Annual Hispanic Heritage Comunidad Award on May 17, 2013. Founder of Friends of Scott Foundation, Carmen Delgadillo, joined one other recipient for a special pre-game ceremony. Friends of Scott Foundation was chosen for its work to improve the lives of families and youths in the San Diego area. The award was presented by San Diego Padres President & CEO Tom Garfinkel.


text:
Published in Oncotarget V9I6, Jan 23, 2018
The prognostic efficacy of cell-free DNA hypermethylation in colorectal cancer
Oncotarget. 2018; 9:7010-7022. https://doi.org/10.18632/oncotarget.24097
Simon Ladefoged Rasmussen _, Henrik Bygum Krarup, Kåre Gotschalck Sunesen, Martin Berg Johansen, Mogens Tornby Stender, Inge Søkilde Pedersen, Poul Henning Madsen and Ole Thorlacius-Ussing
Simon Ladefoged Rasmussen1,2,3, Henrik Bygum Krarup2,4, Kåre Gotschalck Sunesen1, Martin Berg Johansen5, Mogens Tornby Stender1, Inge Søkilde Pedersen2,4, Poul Henning Madsen2,4 and Ole Thorlacius-Ussing1,2,3
1Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark
2Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
3Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
4Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
5Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark
Simon Ladefoged Rasmussen, email: [email protected]
Keywords: colorectal cancer; DNA hypermethylation; prognosis; staging
Received: September 08, 2017 Accepted: January 03, 2018 Published: January 09, 2018
Epigenetic alterations in colorectal cancer (CRC) cause important differences in the underlying tumor biology and aggressiveness. DNA hypermethylation is central for the development of CRC but the prognostic impact remains elusive. We aimed to assess the association between cell-free hypermethylated DNA and stage and survival in colorectal cancer (CRC).
We analyzed pre-treatment plasma samples from 193 patients with CRC. Thirty gene-promoter regions were analyzed using methylation specific PCR. We compared the median number (range) of hypermethylated promoter regions with CRC stage, and constructed a multivariable Cox-regression model adjusted for stage, to evaluate the added prognostic information.
The median number of hypermethylated promoter regions was nine (0-28) in patients with distant metastasis compared to five (0-19) in patients without metastatic disease (p < 0.0001). The majority of the hypermethylated promoter regions inferred a poor prognosis. Cox-regression analysis adjusted for patient age, sex, pre-treatment CEA-levels, and disease stage, showed that RARB (HR = 1.99, 95% CI [1.07, 3.72]) and RASSF1A (HR = 3.35, 95% CI [1.76, 6.38]) hypermethylation inferred a significant effect on survival.
The risk of metastasis increase with the number of cell-free hypermethylated promoter regions. The presence of RARB and RASSF1A hypermethylation indicated aggressive disease, regardless of stage at the time of diagnosis.
Colorectal cancer (CRC) is the third most common cancer worldwide, with more than 1.3 million cases annually [1]. Approximately 90% of patients have potentially curable disease at the time of diagnosis, however, 20-30% will experience local, regional, or metastatic recurrence [2]. Survival of CRC patients is closely related to the stage of disease at the time of diagnosis, with five year survival of 90% in stage I disease versus 13% in patients with stage IV disease [3]. However, even in early stage cancers, patients still experience death due to recurrence. Other prognostic tools could aid in the selection of patients who would benefit from more aggressive treatment regimens.
Sporadic CRC develops through the adenoma to carcinoma sequence, through which individual cancer cells accumulate numerous genetic and epigenetic alterations [4, 5]. Commonly, the initiating genetic event involves silencing or activation of genes involved in cell-fate, cell survival, and genomic stability [6, 7]. These molecular alterations are clonal in nature, giving rise to inter- and intratumor heterogeneity. As with tumor initiation, the molecular changes associated with CRC progression seem to be distinct. However, no consistent epigenetic/genetic alterations have been discovered, which could provide further reliable prognostic information supporting the current staging methods for CRC [8]. The most prevalent epigenetic event in cancer development is DNA promoter hypermethylation [9]. This involves the addition of a methyl-group to a cytosine preceding a guanine in the DNA strand. Hypermethylations primarily target the promoter regions of different tumor suppressor genes leading to decreased transcription and inactivation [10]. Based on tissue studies, a distinct molecular subtype of CRC with increased promoter methylation in a subset of promoter regions was characterized as the CpG island methylator phenotype (CIMP) [11, 12]. This subtype was later characterized by right sided tumors and microsatellite instability [12]. Based on CIMP, previous studies have shown that CRC with this molecular subtype, have decreased overall survival [13].
Other hypermethylated promoter regions have been suggested as blood-based detection markers for CRC. However, only few of the blood based hypermethylations have been investigated for their prognostic value [14]. We aimed to assess a larger panel of cell-free DNA hypermethylations in peripheral blood samples as a marker for stage and survival in CRC patients.
Review of patient records lead to the exclusion of seven patients with benign disease or absence of CRC; three lacked CRC after endoscopic resection, one initially refused surgery, and one never provided informed consent. Moreover, five patients were excluded, because the reference gene (MEST1) could not be amplified during PCR. This left 193 CRC patients from which pre-treatment plasma samples were available for the analysis of cell-free DNA hypermethylations.
DNA hypermethylations and stage
The general characteristics of the CRC patients, along with the median number of hypermethylated promoter regions in plasma according to the respective clinicopathological features, are provided in Table 1. There was no association between the number of hypermethylated promoter regions, and sex or age of the patient population. Elevated CEA levels were positively associated with a high median number of hypermethylated promoter regions. The median levels of cell-free DNA were 4.00 ng/ml (range [0-132.58]) for all patients and highly similar between stages (p = 0.130). The median number of hypermethylated promoter regions in CRC patients with distant metastasis was 9 (range [0, 28]) compared to all other CRC patients with a median number of hypermethylations of 5 (range [0, 19]) (p<0.0001). There was a trend towards an increase in the number of hypermethylations in patients with advanced tumor invasion and advanced nodal status, however, this increase was not statistically significant (Table 1). The number of hypermethylated promoter regions according to AJCC stage is visualized in Figure 1.
Table 1: No. of methylated promoter regions according to clinicopathological features
Methylations, median (range)
5(0-28)
91(47.15)
102(52.85)
Smoke status
Never smoker
Current smoker
Previous smoker
5(2.59)
5(4-8)
CEA-levels
≤ 5 ng/ml
> 5 ng/ml
Tumour
3.5(0-11)
T-unknown
22(5-25)
N-unknown
The number (n) and percentages (%) of colorectal cancer patients according to their respective clinicopathological features and the tumour (T), node (N), and metastasis (M) system. The median number and range of methylated promoter regions (Methylations) are also presented with p-values according to the different clinicopathological features. TNM-staging was performed after surgery from the pathological sections. P-values are calculated using the Wilcoxon-Mann-Whitney test. The P-value for T-stage was calculated to distinguish T1/2 tumours from T3/4 tumours. The P-value for N-stage was calculated to distinguish N0 from N1/2 disease. The P-value for M-stage, was calculated to distinguish M0 from M1 disease.
Figure 1: DNA promoter hypermethylations according to AJCC stage. The number (0-30) of hypermethylated promoter regions – measured in plasma – according to The American Joint Committee on Cancer (AJCC) colon and rectum cancer staging system, 7th Edition. The horizontal line represents the median value. The box shows the upper and lower quartile with the whiskers representing the greatest value, excluding outliers (circles).
Hypermethylation status of each individual promoter region according to the AJCC stage is provided in Table 2. There was a marked increase in the frequency of promoter hypermethylation in all genes from stage I to stage II, however, for several gene promoter regions (e.g. APC, MLH1, NPTX2, and TAC1) there were a marked decrease in methylation frequency from stage II to stage IV CRC (Table 2).
Table 2: Promoter hypermethylations according to CRC stage
AJCC stage 7th edition
ALX4
BMP3
BNC1
CDKN2A
HLTF
MLH1
NDRG4
NPTX2
NEUROG1
OSMR
PHACTR3
PPENK
RARB
RASSF1A
SDC2
SEPT9
SFRP1
SPG20
THBD
TFPI2
WIF1
The number (N) and percentages (%) of colorectal cancer (CRC) patients (N=193) with positive amplification of hypermethylated promoter regions in plasma samples according to the American Joint Committee on Cancer (AJCC) staging system 7th Edition.
DNA hypermethylations and survival
Each patient was followed until death or five years after diagnosis. No patients were lost to follow-up, and the registered overall mortality was 38.3% (74/193). Overall survival was closely associated with the number of hypermethylated promoter regions (Figure 2A). Having more than four methylated promoter regions in plasma, was clearly associated with a decrease in five-year survival (p < 0.001). The association between decreased survival and having five to ten methylated promoter regions in plasma compared to having more than ten hypermethylations was limited (p = 0.09).
Figure 2: Cumulative survival probability according hypermethylation status. (A) Kaplan Meier estimates visualising the effect of the number of hypermethylations on the survival of CRC patients. The solid line represents patients with 0-4 hypermethylated promoter regions measured in plasma. The dashed line represents patients with 5-10 hypermethylated promoter regions in plasma. The short dashed line represents patients with more than 10 hypermethylated promoter regions in plasma. The number of patients at risk in the three groups can be seen below the graph. (B) Kaplan Meier estimates visualising the effect hypermethylation of RARB or RASSF1A on the survival of all-stage CRC patients. The solid line represents patients without hypermethylation of either promoter region. The dashed line represents patients with hypermethylated RARB and/or RASSF1A in plasma. The hazard ratio (HR) was computed using univariable Cox regression (the 95% confidence interval is reported in brackets). The Log-rank test for equality of survivor functions was used to compute the p-value. The number of patients at risk for the two groups can be seen below the graph.
Most of the hypermethylated promoter regions inferred a poor prognosis; however, not all were significant (Figure 3). We chose a strict significance level (P < 0.01) for the selection of potential predictor variables to include in our multivariable Cox-regression model (Table 3). The multivariable Cox-regression model showed, that only two markers were significant independent predictors of poor overall survival when we adjusted for sex, age, pre-treatment CEA-levels, and stage of CRC at the time of diagnosis. These were RARB (HR = 1.99, 95% CI [1.07,3.72]) and RASSF1A (HR = 3.35, 95% CI [1.76,6.38]). The overall effect of RARB and RASSF1A hypermethylation was not affected by tumor localization (colon vs. rectum), and the survival curve for all types of CRC is visualized in Figure 2B.
Figure 3: The individual effect of each promoter hypermethylation on overall survival. Forrest plot visualizing the hazard ratios for all stage CRC patients (N=193). The name of each individual hypermethylated promoter regions is presented on the left, with the corresponding hazard ratio on the right. The bottom horizontal line shows the hazard ratios from 0.6 to 7.2, with the vertical solid line representing the reference line (hazard ratio = 1).
Table 3: Cox regression analysis
Univariable Cox regression
Multivariable Cox regression
Stage I
Stage II
Stage III
Stage IV
The univariable analysis of overall mortality using univariable Cox regression analysis. Variables reaching af significance level (p-values < 0.01) were analysed in the subsequent multivariable Cox regression analysis, adjusting for sex, age, CEA-levels and American Joint Committee on Cancer (AJCC) staging system. Individual hazard ratios (HR) with corresponding 95% confidence intervals (95% CI) and P-values. Carcinoembryonic antigen (CEA) was considered positive if the levels were above 5 mg/l for non-smokers, and if the levels were above 10 mg/l for smokers.
Increased attention has been on DNA alterations, as markers for both disease stage and response to therapy, in cancer. Solid tumors (such as CRC) harbor multiple genetic and epigenetic alterations, which are not detectable in normal cells, making them ideal biomarkers for disease stage and progression. Circulating DNA and circulating tumor cells have therefore been coined the liquid biopsy making an accurate characterization of patient tumors possible, surpassing the need for tumor tissue.
It has long been recognized, that the concentration of circulating cell-free DNA is greater in cancer patients than in healthy control individuals [15, 16]. The concentration is also closely related to tumor burden and the risk of metastasis [16]. To our knowledge, this is the first study to show, that the mere number of hypermethylated DNA fragments is associated with increased risk of metastasis and decreased overall survival. Moreover, we show that the number of methylated promoter regions circulating cell-free DNA only increases from stage I to stage IV CRC. This demonstrates that DNA hypermethylation is a dynamic process, which is closely related to the metastatic properties of CRC.
Not all of the hypermethylated promoter regions were markers for increasing CRC stage. Surprisingly, certain DNA promoter regions were more frequently hypermethylated in stage II vs. stage IV disease. Some of these alterations might indicate less aggressive tumors, or simply be passenger alterations, without any relation to tumor progression [17].
Molecular biomarkers for human malignancies are currently the subject of vigorous investigation [18]. These markers have previously been shown to be more accurate biomarkers than current protein-based biomarkers, and new and improved methods for high-throughput analysis of multiple molecular biomarkers are now available [19]. In castrate-resistant prostate cancer it has been shown, that hypermethylated GSTP1 is a more sensitive predictor for disease progression than the established biomarker; prostate specific antigen (PSA) [20]. This is in line with the results from our multivariable analysis, were we show, that hypermethylated biomarkers render more prognostic information than CEA levels. Furthermore, we found that hypermethylation of RARB and RASSF1A were independent predictors of poor overall survival in CRC patients, further emphasizing the potential usage of circulating hypermethylated DNA as biomarkers for CRC prognosis.
RASSF1A hypermethylation has been implemented in the progression of several different malignancies, the most studied being breast and lung cancer [21]. However, studies have also focused on the association of RASSF1A hypermethylation and CRC. In one study by Shihan et al. RASSF1A promoter hypermethylation was reported in 47% of colorectal tumors versus 13% of paired normal tissue specimens, with significant associations between methylation status and tumor stage, metastasis, and lymphatic invasion [22]. Three studies have assessed its performance as a blood-based biomarker for CRC with sensitivities ranging from 23% to 93% [23–25]. RASSF1A hypermethylation was only present in 11% (22/193) of the plasma samples from our cohort. The discrepancy between our study and the previously mentioned studies could be a result of differences in study population, ethnicity, choice of medium for analysis (plasma vs. serum), and the method used for methylation analysis. However, it seems unequivocal, that circulating hypermethylation of RASSF1A is an indication of aggressive tumors, with a strong risk of metastasis.
The loss of RARB expression has been associated with a variety of cancers (predominantly of mammary and pulmonary origin), and it has been correlated with suppressed expression of epidermal growth factor receptor (EGFR) [26]. EGFR antibodies (e.g. cetuximab or panitumumab) are currently a part of the chemotherapeutic regimen for locally advanced and metastatic CRC, and circulating RARB hypermethylation could therefore be a marker of anti-EGFR resistant disease [27]. Conversely, cell-free hypermethylated RARB has previously been demonstrated in 69.6% of colonoscopy verified healthy individuals, making the function of circulating RARB hypermethylation somewhat puzzling [28]. In pulmonary tumors, hypermethylation of RARB was differentially associated with the development of secondary primary lung tumors, depending on patient smoking status [29]. In our study, there was no apparent association between RARB methylation and smoking status, but this illustrates, that the effect of circulating RARB hypermethylation on patient outcome could be influenced by numerous endogenous as well as exogenous factors not accounted for in this study. We therefore employ, that future studies on circulating cell-free DNA hypermethylations explore the effect of other factors, rather than merely the presence of these molecular biomarkers. This is further stressed in a study by Ørntoft et al. describing SEPT9 [30]. They found, that SEPT9 hypermethylation was readily affected by both the presence of other simultaneous diseases and advanced age. Nonetheless, circulating RARB and RASSF1A hypermethylation appear to be associated with adverse outcome regardless of patient age and disease stage at the time of diagnosis. The effect of especially circulating RARB hypermethylation in a population without CRC remains to be elucidated.
Some limitations in our analytical framework needs to be addressed.
Circulating cell-free DNA does not solely originate from malignant cells. The majority is derived from the turnover of normal cells, or other cells from the tumor micro environment [18]. The DNA from these cells has a number of properties which enables the distinction between "normal" circulating DNA and circulating tumor DNA (e.g. fragment lengths, promoter methylation and somatic mutations) [18]. The consensus molecular subtypes of CRC have recently been established, with the aim of better understanding the non-random process of CRC initiation and progression [31]. Herein, hypermethylation of the 5' untranslated region of different genomic regions has primarily been reported as an event contributing to the initiation and progression of the consensus molecular subtype 1 (CMS1). This subtype accounts for approximately 14% of CRC cases. However, DNA hypermethylation is readily a part of every type of CRC, and different markers could infer different prognostic effects, regardless of the individual tumor subtype.
This was a retrospective analysis of blood samples from a previous study, and tumor samples were not available for this patient cohort. It was therefore not possible to ensure, that the circulating DNA hypermethylations were originating from CRC tumors other than associations from previous studies [14]. Previous studies on metastatic CRC have reported that circulating cell-free DNA is an accurate measure for disease burden [32]. Whether our results are merely a surrogate marker for an increased concentration of circulating DNA is unknown. However, regardless of origin, the presence of a large number of cancer associated hypermethylated DNA fragments is a marker for increased stage, and poor overall survival in CRC patients.
The sensitivity for the detection of hypermethylated DNA could be limited. The DNA is subject to degradation in every analytical step, the most crucial being the bisulfite conversion [33]. This problem is emphasized in the analysis of circulating tumor derived DNA. Circulating tumor DNA is associated with shorter fragment lengths, even more susceptible to degradation than DNA from other sources [18]. The method employed by our group has a reasonable yield of up to 60% after bisulfite conversion [34]. Unfortunately, the yield can be highly variable and the DNA concentration could be reduced by up to 25% after bisulfite conversion. Prolonged storage also leads to a decrease in DNA quantity, with annual degradation rates of approximately 7-30% (at minus 80°C) [35, 36]. Consequently, the false negative rate is strongly affected by the amount of DNA available for analysis. The use of more sensitive digital PCR based methods could provide an even more accurate determination of the hypermethylated DNA fragments even in the situation of low DNA concentrations [37]. Recent developments in sequencing based technologies, could eliminate the need for bisulfite conversion all-together, rendering more DNA for analysis, and hence, less false-negative results [38].
Through this study, we investigated the properties of circulating DNA hypermethylations and their relation to CRC stage and survival. Hypermethylated DNA has been proposed as diagnostic and prognostic markers for CRC. We found that a high number of hypermethylated promoter regions measured in plasma was strongly associated with the presence of distant metastasis and decreased survival in CRC. When incorporated in a multivariable cox regression model, hypermethylated RARB and RASSF1A rendered prognostic information regardless of disease stage at the time of diagnosis. To ensure reproducibility, the results needs to be validated in independent patient cohorts.
In spite of improved screening modalities and treatment strategies, disease recurrence and distant metastasis remains a challenge in CRC treatment. Therefore, analysis of hypermethylated DNA, along with other prognostic markers for CRC (e.g. KRAS mutation and BRAF mutation) could aid in the choice of treatment for these patients.
The study consist of two parts; (i) a cross-sectional study to evaluate the correlation between the number of cell-free DNA hypermethylations and the primary stage of CRC, and (ii) a cohort study to evaluate the impact of cell-free DNA hypermethylations on patient survival.
Consecutive CRC patients admitted for intended curative treatment at The Department of Gastrointestinal Surgery, Aalborg University Hospital between 2003 and 2005 were included prospectively [39]. The original study was conducted in order to evaluate the correlation between CRC and venous thromboembolism. Criteria for inclusion, and exclusion, are described elsewhere [39]. All patients had blood drawn at the time of diagnosis and before the initiation of any treatment. Patient tumors were classified according to the tumor, node, and metastasis (TNM) system, and individual cancers were staged according to the American Joint Committee on Cancer staging system (AJCC) 7th Edition. Stage classification was conducted according to pathology in the patients receiving curative resection and according to radiology in patients who were deemed inoperable.
Written informed consent was obtained from all patients, and the initial study was approved by The North Denmark Region Committee on Health Research Ethics (N-20040067). The subsequent hypermethylation analysis was also approved by The North Denmark Region Committee on Health Research Ethics (N-20140064) and registered at ClinicalTrials.gov (NCT02928120).
Outcome and predictor variables
In order to establish a model for CRC prognosis, we evaluated 30 gene promoter regions, previously analyzed in stool or blood, as biomarkers for stage and survival of CRC patients [14]. These 30 gene promoter regions were defined as the potential prognostic variables (Supplementary Table 1). We handled all potential prognostic variables as dichotomous (hypermethylated/non-hypermethylated). We handled patient sex as a categorical variable and age as a continuous variable. Carcinoembryonic antigen (CEA) was considered positive if the levels were above 5 ng/ml for non-smokers, and above 10 ng/ml for smokers. We defined the outcome variable as time from study inclusion to death (or censoring) for survival analysis.
Blood sampling
All blood samples were obtained by a skilled technician in full accordance with The European Concerted Action on Thrombosis (ECAT) procedures [40]. The blood samples were centrifuged (at 4 °C for 20 minutes at 4000 rpm) immediately after venipuncture, and the EDTA plasma aliquots were collected, and stored at −80°C.
Hypermethylation analysis
The method used for DNA extraction and methylation analysis is based on a rapid bisulfite method [34]. Plasma nucleic acids were extracted from 350-1,000 μl plasma samples using the easyMagTM platform (NucliSens® [bioMérieux SA, France]) according to the manufacturers' instructions. The purified nucleic acids were eluted in 35 μl elution buffer (NucliSens® [bioMérieux SA, France]). Thirty μl DNA extract was then mixed with 60 μl deamination solution, deaminated for 10 minutes at 90 °C, following a purification step and lastly eluted in 25 μl 10 mM KOH. The remaining five μl were used for quantitation. In order to enrich for methylated DNA which had been successfully deaminated, we conducted a first round polymerase chain reaction (PCR) using a mix of methylation specific outer primers for all the investigated promoter regions. The reaction buffer (25 μl) consisted of PCR buffer, 13 μM MgCl2, 0.6 mM dNTP, 250 nM of each outer primer, 1.5 U Taq polymerase (Bioline® [Taunton, MA, USA]), and 0.3 U Cod Uracil-DNA Glycosylase (ArcticZymes® [Tromsoe, Norway]). We distributed the first round reaction mix to individual 200 μl PCR tubes, which were incubated for five minutes at 37 °C, followed by 95 °C for five minutes, and cooled to room temperature. Thereafter, we added 25 μl of purified deamination product to each tube, and performed the PCR reaction for 20 rounds (92 °C for 15 seconds, 55 °C for 30 seconds, and 72 °C for 30 seconds). For the second PCR reaction, we distributed 10 μl buffer containing 0.4 μM methylation specific inner primers and probes in 30 individual wells (one for each promoter region) in a 96 well PCR plate. We added 10 μl of the first round PCR product to 710 μl preincubated reaction mix (37 °C for five minutes and 95 °C for 10 minutes) containing PCR buffer, 250 μM dNTP, 10 μM MgCl2, 8 U Taq polymerase (Bioline®, [Taunton, MA, USA]), and 0.8 Uracil-DNA Glycosylase (Invitrogen® [Waltham, MA, USA]). Twenty μl of reaction mix was then added to each of the 30 wells containing primers and probes. Real time PCR was conducted for 45 rounds (94 °C for 15 seconds, 55 °C for 30 seconds, and 72 °C for 30 seconds). All primer and probe sequences along with amplicon sizes are available in Supplementary Table 2-3.
Initially, we compared the median level of cell-free DNA according to stage of disease at the time of diagnosis using Kruskal-Wallis test. Subsequently, we calculated the number and range of the hypermethylated promoter regions according to CRC stage and TNM classification. The non-parametric Wilcoxon-Mann-Whitney test was used to evaluate if the number differed between high and low stage or TNM classification (T3/4 vs T1/2, N1/2 vs N0, M1 vs M0). We used the Kaplan Meier method to visualize the effect of the number of promoter hypermethylations measured in plasma, and compared the survival distributions using the Log-Rank test. In order to evaluate each of the potential predictor variables as markers for CRC survival, we conducted a univariable Cox regression analysis. All the potential predictor variables reaching a significance level below 0.01 were subsequently examined using multivariable Cox-regression analysis. We constructed a model using the selected predictor variables from the univariable screening, the co-variables sex, age, and pre-treatment CEA levels (>5 ng/ml), adjusted for AJCC stage, in order to evaluate the gained information from the potential predictor variables.
We used STATA® V.13.1 (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP) for all statistical analyses.
The authors extend their gratitude to all participants in the study for providing sample material for analysis. Moreover, the authors wish to thank Bioanalyst June Lundtoft for her invaluable assistance.
The authors have none to disclose.
This study was primarily funded by Aalborg University and Aalborg University Hospital. Grant support was received from "Region Nordjyllands Forskningsfond", "Heinrich Kopps Legat", and "Eva og Henry Frænkels Mindefond".
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Ero-Foto – polski ilustrowany kwartalnik o tematyce fotograficznej, wydawany w Poznaniu w latach 1935–1938.

Historia
Kwartalnik Ero-Foto był ilustrowanym czasopismem poświęconym fotografii amatorskiej, ukazującym się wiosną, latem, jesienią, zimą. Był agendą poznańskiej Wytwórni Fotochemicznej Ero.

Zawartość czasopisma w dużej części stanowiły aktykuły (felietony) kierowane do fotoamatorów (porady odnoszące się m.in. do poprawnej ekspozycji, poprawnej kompozycji). Oddzielną część czasopisma stanowiły artykuły o fotografii, estetyce w fotografii, artykuły poświęcone technice, chemii fotograficznej oraz opisom sprzętu fotograficznego. Część czasopisma stanowiła rubryka zajmująca się oceną fotografii nadesłanych przez czytelników (Kącik krytyczny). Na łamach kwartalnika Ero-Foto organizowano cykliczne konkursy fotograficzne dla czytelników. Inną część kwartalnika poświęcono na aktualne wiadomości nawiązujące do fotografii (wydarzenia, wystawy, konkursy), wiadomości o pracy krajowych stowarzyszeń fotograficznych oraz informacje o pracy (działalności) poznańskiej Wytwórni Fotochemicznej Ero. Kolejną stałą rubryką w Ero-Foto była Prasa Krajowa – przegląd krajowej prasy o tematyce fotograficznej (m.in. Fotograf Polski, Przegląd Fotograficzny, Wiadomości Fotograficzne).

Kwartalnik był pismem otwartym na współpracę z czytelnikami – na łamach pisma zachęcano czytelników do nadsyłania artykułów oraz zdjęć. Wiele miejsca poświęcono na prezentację zdjęć polskich fotografów (na kilku oddzielnych stronach kwartalnika publikowano reprodukcje zdjęć, nawiązujących tematyką do artykułów opublikowanych w czasopiśmie, reprodukcje fotografii wyróżnionych w konkursach Ero-Foto) oraz reklamę nawiązującą do tematyki fotograficznej.

Redaktorem prowadzącym czasopisma był Zenon Maksymowicz – m.in. wiceprezes Zarządu Poznańskiego Towarzystwa Fotograficznego.

Przypisy

Czasopisma w języku polskim
Czasopisma w Polsce (1918–1939)
Czasopisma wydawane od 1935
Czasopisma wydawane do 1939
Kwartalniki wydawane w Poznaniu
Niewydawane kwartalniki polskie
Polskie czasopisma o fotografii
Prasa w Poznaniu (II Rzeczpospolita)


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Paper Tiger (Edinburgh): Stockists of my SIGNED books and cards.


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Top five award destinations for May
Frequent Flyer Jun 26, 2008
Wondering where to go with all those frequent flyer miles? If you know where to look, the airlines will help you choose flights with seats readily accessible to mileage program members.
In response to the outcry from mileage collectors frustrated by the lack of available award seats, the airlines are attempting to steer program members in the direction of flights that are good prospects for would-be award travelers, both by listing destinations with plenty of empty seats (hot spots) and by discounting award flights to lower-demand destinations.
Some of these flights are running just half-full for good reason: they're dogs. Winnipeg in February? Thanks, but no thanks.
But among the throwaways are some real gems. Following are five award destinations the airlines are promoting for the coming month that merit special attention and are well worth your miles.
(While not all airlines currently offer hot spot lists, the suggestions of those that do should be a fairly good proxy for award availability on other airlines.)
The top five picks for May 2008:
1. Chicago, IL
The Windy City in winter? Too cold. And during the summer months, Chicago is too hot. But springtime in Chicago is just right.
Both American and United have award seats available for Chicago flights.
2. Cleveland, OH
Thanks to Continental, flights to and from Cleveland are good prospects for award travel this spring.
Continental recently expanded its presence at Cleveland Hopkins International Airport, and has put a slew of double-mile promotions in effect to help spur sales.
General rule: If airlines are offering bonus miles to fill flights to a particular destination, there are very likely to be seats available for frequent flyer awards. And if one carrier is having trouble filling seats to that destination, other carriers are almost certain to be similarly challenged.
3. London, England
It will be tough to book a flight to London this summer. But for now, there's more supply than demand, making it a buyers' market. Northwest is offering bonus miles to fill some of its London flights, as is American. And United shows award availability to Heathrow from its Chicago, Denver, Los Angeles, and Washington, D.C., hubs
So take advantage of the current weak demand to use miles for a free trip to one of the world's great cities. The window of opportunity closes soon.
4. San Jose, Costa Rica
For something a little different, consider redeeming miles for a visit to San Jose, the capital of Costa Rica, the country known as the Switzerland of Latin America for its peaceful ways and high standard of living.
A third of the country's population resides in the greater Costa Rica metro area, one of the most cultured and cosmopolitan in the region. And outside the city, ecotourism flourishes.
American is featuring San Jose on its hot list for May.
5. Papeete, Tahiti
And finally, for something truly exotic, we re-recommend a discounted award to the South Pacific.
Through May 31, members of American's AAdvantage program can redeem 30,000 miles (rather than the 75,000 normally required) for a round-trip coach flight between New York and Papeete, Tahiti, on Air Tahiti Nui. That's exceptional value.
There's one drawback to this offer: The 30,000-mile award does not include a connecting flight to New York. But even if you had to purchase a cheap ticket from your hometown airport to connect with an Air Tahiti flight at New York's Kennedy Airport, this would be a deal worth serious consideration.


This video is absolutely jaw dropping.
Folks that develop systems, such as on board computer networks in vehicles or medical systems, that allow access via wire or wireless need to rethink the way those systems are made.
Fellow MVP Dana Epp also has some great security related videos that include simple step-by-step instructions on how to get past system security.
It's getting to the point where the only "secure" way to live is to build a log cabin somewhere with a faraday cage and no inbound/outbound connections whatsoever. Note that there needs to be tree cover to deep keep the eyes in the sky out too.
Getting to know the risks is a part of what we do.


text:
An area organization enables to build regions from any spatial pattern, existing administrative division, or created artificially from social interactions.

Groups behavior for territorial areas like Archipelagos, Outermost regions, traditional divisions (Melanesia, Polinesia, etc), Capes, Channels, Peninsulas, etc.

Examples

(TRegionOrganization @ 'Caribbean') sortedTerritoryNames