*2.4. Processing Framework*

The processing framework applied to each HS cube is composed by the following steps. First, a standard flat field correction is applied to the images. To this end, the images are transformed from radiance to normalized transmittance by using a reference image that is captured from a blank area of the pathological slide [23]. Then, due to the high correlation of spectral information between adjacent spectral bands, a reduced-band HS image is generated by averaging the neighbors' spectral bands, reducing the number of spectral bands from 826 bands to 275 and slightly reducing the white Gaussian noise. This band reduction is also beneficial for alleviating computational cost in the subsequent image processing. Finally, each image is divided into patches, which will train the CNN. In this section, we will detail the architecture of the proposed neural network, the metrics that are used for performance evaluation, and the proposed data partition scheme.


*2.1. Participants*

The invitation letter and consent form were sent out by habilitation services across Norway to the registered parents of each child with Down syndrome who was scheduled to start school. Parents of 43 children with Down syndrome accepted the invitation and returned the consent form to the principal investigator. In their acceptance, they also confirmed that their child did not have any known comorbid diagnoses of autism spectrum disorder and that Norwegian was the child's first language. Of the 43 children with Down syndrome, two participants were excluded because of missing data regarding difficulties with speech fluency. Thus, the final sample consisted of 41 participants (21 boys and 20 girls) with a chronological age of *M* = 75.79 months (*SD* = 3.57 months) and a raw non-verbal mental ability score (block design) of *M* =12.32 (*SD* = 5.51). In addition, parents of 57 typically developing children with similar non-verbal mental abilities accepted the invitation to serve as controls. These children were recruited from eight kindergartens in a Norwegian municipality; they were required to have Norwegian as their first language and no history of special educational needs. Of the 57 typically developing children, 3 participants were excluded due to missing data on the dependent variable. The final sample of typically developing children consisted of 54 participants (26 boys and 28 girls; chronological age: *M* = 36.50 months, *SD* = 4.15 months; non-verbal mental ability raw score (block design): *M* = 12.57, *SD* = 4.48).


**Abstract**

Sustainability, regulation and environmental issues such as climate change and resource scarcity are emerging as key trends with decisive impact on company's Risk management, value creation and growth strategy. This combination represents one of the biggest opportunities to Society as a whole, including organizations, Governments and citizens. Typically, companies possess vast amounts of data, most of it unutilized. Many are now making investments in digital transformation, which generates even more data. The issue is how to generate social impact returns. The use of data and data analytics is centuries old, but with Artificial Intelligence (AI), Machine Learning (ML), jointly with other distributed ledger technologies (Blockchain, Cloud) that are advancing rapidly, there are major opportunities to capture value better, cheaper and faster. Speed is of the essence, and success depends on how fast organizations understand the need for non-financial risks management and respond to data-driven intelligence by reallocating resources to accomplish what needs to be done more efficiently. The reason for impact returns is understanding the benefit as a common value, not exclusive to companies, but it also has to distribute value among individuals, communities, and why not, to contribute to regenerate our planet based on a new economy.

**Keywords:** Social Impact Return, Sustainability, Risk Management, Data Science, Quantitative Modeling, Competitive Intelligence, ESG, Advanced Analytics, Profit Enhancement


**5.1 Sleep hygiene**

Sleep hygiene involves basic education on how the sleep environment, caffeine, alcohol, nicotine, food and exercise affect sleep (Smith et al., 2002). Sleep Hygiene is an educational approach designed to teach insomnia patients as well as the population at large how to maintain healthy behavioral habits which promote better sleep. It is important to understand that successful treatment is only possible if the patient complies with suggestions to improve sleep hygiene (*Edinger et al., 2001)*. Below are summarized tips for sleep hygiene

### *Sleep hygiene tips*

Sleep in Patients with ESRD Undergoing Hemodialysis 419

Structured exercise programs may also improve symptoms of insomnia (Montgomery & Dennis., 2004). Despite the promise of CBT the relative efficacy of these various nonpharmacologic approaches has not been well established. Data also suggest that CBTin contrast to medications may have a lasting effect beyond the termination of treatment. The extent to which the concomitant use of nonpharmacologic therapy augments the performance of pharmacologic treatments needs to be established in further studies (Novak et al., 2006).

Stimulus-control therapy is a behavioral approach based on the premise that some sleep disturbances are behaviorally conditioned, so that the patient associates the bedroom environment with arousal. The main objective of stimulus control therapy is to reassociate

If not asleep within about 10 minutes, patient gets out of bed, and does not return to

Bed is used only for sleeping (not for watching television, reading exciting books, etc).

This method focuses primarily on shortening sleep onset, however, in the case of sleep maintenance insomnia, the instructions may be followed when the patient awakens and cannot fall back to sleep during the night. The patient should avoid lying awake in bed as much as possible and only go to bed when sleepy. No stimulating or distracting activities (e.g. reading exciting books or articles, watching television, looking at a clock) should be available. Although the patient cannot control sleep onset, wake up time should be fixed, so that a regular sleep/wake schedule will develop. Pro hibiting daytime naps is important to take advantage of the sleep deficit accumulated since the sleep period on the previous night, which in itself can shorten sleep onset. As with all psychological therapies, compliance is

Stimulus control therapy has been shown to be effective in shortening sleep latency compared with placebo intervention in insomnia patients (Lacks, Bertelson, Gans & Kunkel, 1996). Clinical trials have documented the efficacy of stimulus control therapy for both sleep

Sleep restriction therapy, is based on the observation that many insomnia patients spend an excessive amount of time in bed in futile attempts to achieve more sleep (Spielman, Saskin, & Thorpy, 1987).. Sleep restriction therapy consists of curtailing the amount of time spent in bed to increase the percentage of time spent asleep. This improves the patient's sleep efficiency (time asleep/time in bed). For example, a person who reports staying in bed for eight hours but sleeping an average of five hours per night would initially be told to decrease the time spent in bed to five hours. The allowable time in bed per night is increased 15 to 30 minutes as sleep efficiency improves. Adjustments are made over a period of weeks

Below are summarized instructions for stimulus-control therapy (Martin, 2000).

When patient returns to bed, if not asleep within 15 minutes, gets out of bed.

enhanced when the instructions and their rationales are explained to the patient.

onset and sleep-maintenance insomnia (Espie et al., 1989; Lacks et al., 1993)

 Pattern is repeated until patient can fall asleep within a few minutes. Must get up at the same time each morning (even if only slept 2 hours).

**5.3 Stimulus-control therapy**

bed until sleepy.

**5.4 Sleep restriction therapy**

the bed and bedroom with the rapid onset of sleep.

*Instructions for Stimulus-Control Therapy*  Patient goes to bed only when sleepy.

All naps during the day must be avoided.

These suggestions often combine several methods and may sound trivial. Compliance with such advice is still relatively poor however as it frequently requires changes in persistent "bad" habits which are ingrained (Morin et al., 1999). Building a regular sleep schedule and creating an appropriate sleeping environment as well as regular physical activity are very important in combating insomnia or insomnia-like presentations in RLS/PLMD (Montgomery & Dennis, 2004).

In terms of sleep hygiene for RLS/PLMD, there are a two main points that bear highlighting. First, the avoidance of alcohol, caffeine and nicotine may be underscored because of their potential contribution to RLS symptoms and/or PLMs. Second, other sleep hygiene practices may or may not have any utility for patients with RLS. Particularly when sleep hygiene is provided to patients as a handout or pamphlet, there is no indication that this helps promote sleep in any patient group. (Martin, 2000; Pigeon &Yurcheshen, 2009).

### **5.2 Relaxation and biofeedback techniques**

Relaxation and biofeedback techniques for treating insomnia are based on the assumption that insomnia patients are overly aroused and anxious, and this interferes with their ability to initiate and/or maintain sleep (Lacks, 1993). Relaxation techniques are designed simply to teach patients to relax, and thus improve their ability to sleep. Of several relaxation methods, none has been shown to be more efficacious than the others. Progressive muscle relaxation, autogenic training and electromyographic biofeedback seek to reduce somatic arousal (e.g., muscle tension), whereas attention-focusing procedures such as imagery training and meditation are intended to lower presleep cognitive arousal (e.g., intrusive thoughts, racing mind) (Spielman et al., 1987).

 In general, biofeedback training is an effective treatment for some insomnia patients, and is as effective as other non-pharmacologic interventions (Morin et al., 1999). If patients can train themselves to relax before sleep or at night after an awakening, they are more capable or falling asleep and staying asleep. It is believed that the beneficial effects of these methods extend beyond the sleep problems in that they facilitate better coping skills in general (Martin, 2000).

Structured exercise programs may also improve symptoms of insomnia (Montgomery & Dennis., 2004). Despite the promise of CBT the relative efficacy of these various nonpharmacologic approaches has not been well established. Data also suggest that CBTin contrast to medications may have a lasting effect beyond the termination of treatment. The extent to which the concomitant use of nonpharmacologic therapy augments the performance of pharmacologic treatments needs to be established in further studies (Novak et al., 2006).


**9. Conclusions**

adjuvant chemotherapy, neoadjuvant chemoradiation, neoadjuvant chemoradiation versus

Concerning toxicity among patients treated with neoadjuvant treatments that have been reported, mostly as local experiences or as small institutional trials, there are no clear data concerning side effects of neoadjuvant therapies, nor there are data on perioperative morbidity and mortality, comparing patients who underwent upfront surgery and patients who received neoadjuvant treatment and then underwent surgery. The biggest data on quality of life come from reports in the metastatic setting. The quality of life report of the PRODIGE-4 trial (mentioned earlier), FOLFIRINOX chemotherapy reduced the quality of life impairment compared with gemcitabine, but also it has benefit in the quality of life that can be a surrogate for survival, as physical functioning and some symptoms severity were prognostic factors for survival [50]. In a meta-analysis of FOLFIRINOX in locally advanced pancreatic cancer, 60% of the patients presented G3 or higher side effects, neutropenia and diarrhea being the most frequent events among treated patients. There were no related deaths attributable to FOLFIRINOX [42]. In a retrospective analysis of patients undergoing FOLFIRINOX as neoadjuvant treatment followed by surgery, Marchegiani et al. concluded that among patients who underwent neoadjuvant chemotherapy, there were less postoperative pancreatic fistula and

less postoperative pancreatic hemorrhage but delayed in gastric emptying [51].

Due to a lack of strong data based on phase 3 clinical trials, it is not possible to talk about a gold-standard treatment in the neoadjuvant setting for pancreatic cancer patients. Most of the groups support the idea to perform surgery as an upfront treatment in resectable patients fol-

Current ESMO guidelines support the use of FOLFIRINOX followed by chemoradiotherapy in borderline resectable patients as a main option in pancreas cancer [52]. Contrarily, ASCO guidelines indicate that there is no clear evidence to support one regimen over another, and physicians may offer therapy based on extrapolation from data derived from studies in the

Pancreatic cancer patients with resectable or borderline resectable disease should always be discussed in a multidisciplinary team. Neoadjuvant treatment should always be considered to attempt an R0 resection; otherwise, the chance of cure in non-R0-resected patients and also due to the meaning of the diagnosis itself will be similar to metastatic patients. Multidisciplinary team should at least include a digestive oncological surgeon with expertise in pancreatic surgery, a medical oncologist, a radiologist with expertise in pancreas, a radiation oncologist, and a pathologist, given the disparity of opinions and the importance of treatment agreement

At SLAGO 2015 (Latin American Gastro-Enterology Cancer Symposium) congress [54], a meeting held every 2 years in Latin America that focuses on digestive malignancies, specialists from different Latin American countries met to discuss about pancreatic cancer. Concerning

upfront surgery, and other modalities as well [45–49].

**8. Current guidelines**

188 Advances in Pancreatic Cancer

metastatic setting [53].

lowed by adjuvant chemotherapy.

looking forward the best chance to those patients.

Pancreatic cancer is one of the most lethal malignancies among all types of solid tumors. Most of the patients are diagnosed at unresectable or at advanced stages with no chances of cure. Early diagnosis is critical to give the patient the chance of cure; however, most of the patients are diagnosed where the tumor is not amenable to be resected. Even more, many of the patients who will undergo an R0 resection will relapse before 2 years after surgery.

We would like to remark that there is no strong evidence to make final conclusions in order to define the best upfront treatment in non-metastatic resectable and borderline resectable pancreatic cancer patients. For resectable patients at diagnosis, upfront surgery is still the standard of care followed by adjuvant chemotherapy. In this subgroup of patients, radiotherapy and chemoradiotherapy do not seem to be the best choice. On the other hand, neoadjuvant chemotherapy has not been explored yet in well-designed clinical trials, and its use has been just limited to small experiences. Borderline resectable pancreatic cancer patients are a subgroup where upfront surgery has a low chance of achieving an R0 resection; therefore, these patients must be considered to receive neoadjuvant treatments in order to improve complete tumor resection and as a consequence to improve survival. As in the resectable subset of patients, radiotherapy or chemoradiotherapy has not shown a real impact in this group. FOLFIRINOX followed or not by chemoradiotherapy seems to be the best option to improve resectability, for achieving complete resection and pathological downstaging and for improving overall survival in resected patients. Final reports from clinical trials will set the key whether or not neoadjuvant treatment, in resectable and borderline resectable pancreatic cancer patients, should be mandatory or recommended.


**4.1 Does output of the basal ganglia modulate sleep?**

Cholinergic neurons in the PPN and laterodorsal tegmental nucleus are thought to be involved in not only the maintenance of arousal state but also generation of REM sleep (Datta and Siwek, 2002; Koyama & Sakai, 2000; Maloney et al., 1999). Therefore, we elucidated how GABAergic SNr-PPN projection altered the activities of the REM generator and the muscle tone inhibitory system (Takakusaki et al., 2004c). Summary of the results are shown in Fig.7. Stimulation of inhibitory region of the PPN induced REM which was associated with muscular atonia in decerebrate cats (REM and atonia; Fig.7Ba). Conditioning

Possible Contribution of the Basal Ganglia

1991; Inglis & Winn, 1995; Jones, 1991).

**4.2.2 Narcolepsy-like symptoms**

PD (Takakusaki 2008).

Brainstem System to the Pathogenesis of Parkinson's Disease 447

Several mechanisms are postulated in relation to the basal ganglia regulation of sleep. On one hand, recent brain imaging studies revealed that damage of brainstem, particularly the reticular formation, is critically involved in the pathogenesis of RBD (Unger et al., 2010). The brainstem damage could also explain some non-motor symptoms in this disease, which often precede diagnosis, such as autonomic dysfunction and sleep disorders. On the other hand, roles of dopaminergic influence on the basal ganglia in the control of sleep-wake behavior are suggested (Mena-Segovia J et al., 2008). It is also possible that basal ganglia efferents to the non-specific thalamic nuclei may affect awake-sleep states by modulating the activity of ascending reticular activating system (ARAS). Since the classical study of Moruzzi and Magoun (1949), the pontomesencephalic reticular formation has been known to comprise the ARAS. The PPN has been considered as a part of the ARAS (Garcia-Rill,

The SNr has a direct projection to the thalamic nuclei (Parent et al., 1983; Pare´ et al., 1990) in addition to the PPN (Fig.7D). Because PPN has dense projections to the midbrain dopaminergic neurons, activity of the PPN neurons may affect awake-sleep states by modulating dopaminergic systems projecting to the basal ganglia and extra-basal ganglia areas. Consequently, our idea is that basal ganglia output from the SNr may affect awake– sleep cycles by modulating the activity of the ARAS through dual mechanisms (Fig.7D). One is through direct nigro-thalamic projection, and the other, which is considered in this study,

The presence in PD patients of narcolepsy-like features, such as daytime REM sleep intrusions associated with visual hallucinations, has led some authors to suggest that a mechanism similar to that of narcolepsy might underlie excessive daytime sleepiness (EDS) in PD (Arnulf et al., 2000). Thannickal et al. (2007) demonstrated that a massive loss of orexin neurons was found in PD patients and suggested that it was a cause of the narcolepsy-like symptoms. However, Compta et al. (2009) showed that orexin-A level was normal in the cerebrospinal fluid and it was unrelated to severity of sleepiness or the cognitive status of PD patients. Therefore alternative mechanisms other than dysfunction of orexin neurons might be responsible for EDS and the disturbance of sleep architecture in PD. In animal experiments, midbrain strucutes, including the SNr, the PPN and the MLR, receive orexinergic efferents from the perifornical lateral hypothalams (Nambu et al., 1999; Peyron et al., 1998). Therefore it is interesting to elucidate how orexinergic projections to the midbrain are involved in alteration of sleep-awake states. Then we examined effects of injections of orexin-A into the MLR, PPN and the SNr upon motor behaviors in decerebrate cats (Takakusaki et al., 2005). Microinjections of orexin into the MLR facilitated locomotion, while those into either the PPN or the SNr suppressed PPNinduced muscular atonia. The latter effects were reversed by subsequent injection of bicuculline into the PPN. Thus the excitability seems to be higher in the locomotor system than in the atonia system in the presence of orexin. On the contrary the excitability of the muscle tone inhibitory system may be higher than that of the locomotor system in the absence of orexin. Accordingly GABAergic projection from the SNr to the PPN/MLR area (BG-BS system) may underlie orexin-mediated vigilance state regulation and its dysfunction may be one of pathophysiological mechanisms of narcolepsy-like features of

is though indirect connections via the PPN (Takakusaki et al. 2004c, 2006).

stimuli applied to the lateral part of the SNr (blue circles in Fig.7C) completely abolished the PPN-induced REM with atonia (Fig.7Bb). On the other hand, stimulation of the SNr, denoted by black squares in Fig.7C, only inhibited REM (Fig.7Bd). It was also observed that stimuli applied to the sites which were indicated by red circles in Fig.7C did not block REM but attenuated the muscular atonia (Fig.7Bc), i.e., REM without atonia (Sanford, 1994), which is considered to be relevant to RBD in human (Culebras & Moore, 1989), was evoked. These findings indicate that neurons in the PPN that are responsible for generation of REM sleep are affected by GABAergic projections from the SNr.

Fig. 7. Possible mechanisms of basal ganglia modulation of REM sleep

A. Experimental design in decerebrate cats. B. (a) Stimulation of the PPN induced REM and atonia. (b) ~ (d) Effects of stimuli applied to various sites of the SNr on the PPN-induced REM and atonia. (b) Stimulation of the sites indicated by blue circles in C inhibited both REM and atonia. (c) Stimulation of the sites indicated by black squares in C. only inhibited REM. (d) Stimulation of the sites indicated by red circles in C inhibited atonia but not REM (REM without atonia). C. Effective sites for modulating the eye movements and muscular atonia were located in the lateral part of the SNr. D. Possible mechanisms of basal ganglia modulation of REM sleep. Abbreviations, ARAS; ascending reticular activating system, REM; rapid eye movement.

#### **4.2 Possible mechanisms of sleep disturbances in Parkinson's disease 4.2.1 Disturbance of REM sleep (REM sleep behavior disorder; RBD)**

Sleep disturbance is one of early signs of PD (Askenasy, 2001**;** Ferini-Strambi & Zucconi, 2000; Larsen & Tandberg, 2001). There are several reports suggesting that nearly half number of PD patients who were diagnosed as idiopathic RBD but free of neurodegenerative diseases had developed PD (Boeve, 2007; Iranzo, 2006; Schenck, 1996). Postuma et al. (2010) conclude that severity of REM atonia loss in idiopathic RBD predicts PD. Neuronal loss in the PPN was reported in PD (Hirsch et al., 1987; Jellinger, 1988; Zweig et al., 1989), and loss of cholinergic neurons in the PPN is possibly related to disability of PD patients (Rinne et al., 2008).

stimuli applied to the lateral part of the SNr (blue circles in Fig.7C) completely abolished the PPN-induced REM with atonia (Fig.7Bb). On the other hand, stimulation of the SNr, denoted by black squares in Fig.7C, only inhibited REM (Fig.7Bd). It was also observed that stimuli applied to the sites which were indicated by red circles in Fig.7C did not block REM but attenuated the muscular atonia (Fig.7Bc), i.e., REM without atonia (Sanford, 1994), which is considered to be relevant to RBD in human (Culebras & Moore, 1989), was evoked. These findings indicate that neurons in the PPN that are responsible for generation of REM

sleep are affected by GABAergic projections from the SNr.

Fig. 7. Possible mechanisms of basal ganglia modulation of REM sleep

**4.2 Possible mechanisms of sleep disturbances in Parkinson's disease 4.2.1 Disturbance of REM sleep (REM sleep behavior disorder; RBD)**

REM; rapid eye movement.

patients (Rinne et al., 2008).

A. Experimental design in decerebrate cats. B. (a) Stimulation of the PPN induced REM and atonia. (b) ~ (d) Effects of stimuli applied to various sites of the SNr on the PPN-induced REM and atonia. (b) Stimulation of the sites indicated by blue circles in C inhibited both REM and atonia. (c) Stimulation of the sites indicated by black squares in C. only inhibited REM. (d) Stimulation of the sites indicated by red circles in C inhibited atonia but not REM (REM without atonia). C. Effective sites for modulating the eye movements and muscular atonia were located in the lateral part of the SNr. D. Possible mechanisms of basal ganglia modulation of REM sleep. Abbreviations, ARAS; ascending reticular activating system,

Sleep disturbance is one of early signs of PD (Askenasy, 2001**;** Ferini-Strambi & Zucconi, 2000; Larsen & Tandberg, 2001). There are several reports suggesting that nearly half number of PD patients who were diagnosed as idiopathic RBD but free of neurodegenerative diseases had developed PD (Boeve, 2007; Iranzo, 2006; Schenck, 1996). Postuma et al. (2010) conclude that severity of REM atonia loss in idiopathic RBD predicts PD. Neuronal loss in the PPN was reported in PD (Hirsch et al., 1987; Jellinger, 1988; Zweig et al., 1989), and loss of cholinergic neurons in the PPN is possibly related to disability of PD Several mechanisms are postulated in relation to the basal ganglia regulation of sleep. On one hand, recent brain imaging studies revealed that damage of brainstem, particularly the reticular formation, is critically involved in the pathogenesis of RBD (Unger et al., 2010). The brainstem damage could also explain some non-motor symptoms in this disease, which often precede diagnosis, such as autonomic dysfunction and sleep disorders. On the other hand, roles of dopaminergic influence on the basal ganglia in the control of sleep-wake behavior are suggested (Mena-Segovia J et al., 2008). It is also possible that basal ganglia efferents to the non-specific thalamic nuclei may affect awake-sleep states by modulating the activity of ascending reticular activating system (ARAS). Since the classical study of Moruzzi and Magoun (1949), the pontomesencephalic reticular formation has been known to comprise the ARAS. The PPN has been considered as a part of the ARAS (Garcia-Rill, 1991; Inglis & Winn, 1995; Jones, 1991).

The SNr has a direct projection to the thalamic nuclei (Parent et al., 1983; Pare´ et al., 1990) in addition to the PPN (Fig.7D). Because PPN has dense projections to the midbrain dopaminergic neurons, activity of the PPN neurons may affect awake-sleep states by modulating dopaminergic systems projecting to the basal ganglia and extra-basal ganglia areas. Consequently, our idea is that basal ganglia output from the SNr may affect awake– sleep cycles by modulating the activity of the ARAS through dual mechanisms (Fig.7D). One is through direct nigro-thalamic projection, and the other, which is considered in this study, is though indirect connections via the PPN (Takakusaki et al. 2004c, 2006).

### **4.2.2 Narcolepsy-like symptoms**

The presence in PD patients of narcolepsy-like features, such as daytime REM sleep intrusions associated with visual hallucinations, has led some authors to suggest that a mechanism similar to that of narcolepsy might underlie excessive daytime sleepiness (EDS) in PD (Arnulf et al., 2000). Thannickal et al. (2007) demonstrated that a massive loss of orexin neurons was found in PD patients and suggested that it was a cause of the narcolepsy-like symptoms. However, Compta et al. (2009) showed that orexin-A level was normal in the cerebrospinal fluid and it was unrelated to severity of sleepiness or the cognitive status of PD patients. Therefore alternative mechanisms other than dysfunction of orexin neurons might be responsible for EDS and the disturbance of sleep architecture in PD. In animal experiments, midbrain strucutes, including the SNr, the PPN and the MLR, receive orexinergic efferents from the perifornical lateral hypothalams (Nambu et al., 1999; Peyron et al., 1998). Therefore it is interesting to elucidate how orexinergic projections to the midbrain are involved in alteration of sleep-awake states. Then we examined effects of injections of orexin-A into the MLR, PPN and the SNr upon motor behaviors in decerebrate cats (Takakusaki et al., 2005). Microinjections of orexin into the MLR facilitated locomotion, while those into either the PPN or the SNr suppressed PPNinduced muscular atonia. The latter effects were reversed by subsequent injection of bicuculline into the PPN. Thus the excitability seems to be higher in the locomotor system than in the atonia system in the presence of orexin. On the contrary the excitability of the muscle tone inhibitory system may be higher than that of the locomotor system in the absence of orexin. Accordingly GABAergic projection from the SNr to the PPN/MLR area (BG-BS system) may underlie orexin-mediated vigilance state regulation and its dysfunction may be one of pathophysiological mechanisms of narcolepsy-like features of PD (Takakusaki 2008).

Possible Contribution of the Basal Ganglia

**5. Concluding thoughts**

**6. Acknowledgment**

**7. References**

0022-510X.

both dopaminergic and cholinergic systems.

Brainstem System to the Pathogenesis of Parkinson's Disease 449

with information relating to reward and reinforcement by modulating the excitability of

The basal ganglia controls various function by acting on thalamocortical loop (C-BG loop) and the brainstem (BG-BS system). There are two key mechanisms for the operation by the basal ganglia circuit. One is sequential information processing, which would enhance the temporal contrast of the excitability of the target systems so that only the selected motor program could be appropriately executed, whereas other competing programs can be cancelled. The other is sustained output from the basal ganglia, which may control the degree of freedom of the excitability of the target systems during movements. We suggest that following roles can be played by the BG-BS system. First this system is involved in the automatic or unconscious control of movements that accompany voluntary movements. Second, the BG-BS systems may be involved in the maintenance of arousal and attentive states and in the regulation of REM sleep. Because output from the basal ganglia is thought to be overactive in PD, dysfunction of the BG-BS system in addition to that of C-BG loop can

This work is supported by Grants-in-Aid for Challenging Exploratory Research (Project # 23650202) and Priority Areas "Emergence of Adaptive Motor Function through Interaction between Body, Brain and Environment (Area #454)" from the Japanese Ministry of Education, Culture, Sports, Science and Technology to K.T. We express sincere appreciation

Aarsland, D., Bronnick, K., Williams-Gray, C., Weintraub, D., Marder, K., Kulisevsky, J.,

Arnulf, I., Bonnet, AM., Damier, P., Bejjani, BP., Seilhean, D., Derenne, JP. & Agid, Y. (2000)

Alessandro, S., Ceravolo, R., Brusa, L., Pierantozzi, M., Costa, A., Galati, S., Placidi, F.,

Andujar, J-E. & Drew, T. (2007) Organization of the projections from the posterior parietal

*Neurology*, Vol. 55, No.2, (July 25), pp. 281-288, ISSN 0028-3878 .

*Neurol.* Vol. 504, No.1, (Sep. 1), pp. 17–41, ISSN 0092-7317.

Burn, D., Barone, P., Pagonabarraga, J., Allcock, L., Santangelo, G., Foltynie, T., Janvin, C., Larsen, JP., Barker, RA. & Emre, M. (2010) Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. *Neurology*, Vol. 75,

Hallucinations, REM sleep, and Parkinson's disease: a medical hypothesis.

Romigi, A., Iani, C., Marzetti, F. & Peppe, A. (2010) Non-motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: focus on sleep and cognitive domains. *J. Neurol. Sci.,* Vol. 289, No. 1-2, (Feb. 15) pp. 44-48, ISSN

cortex to the rostral and caudal regions of the motor cortex of the cat. *J. Comp.*

be seriously involved in motor and non-motor functions in this disease.

No.12,(September 21), pp. 1062-1069, ISSN 0028-3878.

to Ms. Mihoko Ebisawa for preparation of this manuscript.

### **4.3 Disturbances of arousal state, attention and cognition**

Behavioral arousal requires an activation of dopaminergic projections arising from the SNc to the striatum and the ventral tegmental area (VTA) to the prefrontal cortex and the limbic system. The nigrostriatal projection is responsible for basal ganglia related motor functions. The mesocortical projection contributes to volitional expression and attention, and the mesolimbic projection is involved in emotional expression. On the other hand, ARAS plays a major role in the electroencephalographic arousal. An activation of the two arousal systems is required to maintain arousal state that enables alert, attention and cognition (Jones 1991). Because PPN has dense cholinergic and non-cholinergic excitatory connections with dopamine (DA) neurons in the SNc and other basal ganglia nuclei (Futami et al., 1994; Kitai, 1998; Takakusaki et al., 1996), these projections appear to play a role in more specific subcortical integration of motor and non-motor functions such as behavioral arousal, attention and reward (Kitai, 1998). For example, an injection of muscimol into the PPN reduced the speed and amount of arm movements and delayed the onset of movements but the accuracy was rather maintained (Matsumura and Kojima, 2001). Moreover, Kojima et al. (1997) demonstrated that kainic acid-induced lesion in the unilateral PPN induced hemiparkisonism which was observed in the contralateral side of the injection. From these findings they suggest that the PPN may thus facilitate the voluntary limb movements through its excitatory connections with the DA neurons.

Midbrain DA neurons are also involved in the predictive reward which is specifically linked with reinforcement behaviors. DA neurons are activated by rewarding events that are better than predicted, remain uninfluenced by events that are worse than predicted (Hikosaka et al., 2000; Schultz, 1998). Kobayashi et al. (2002) demonstrated that PPN neurons showed multi-modal activities during saccade tasks in alert monkey; their activities were related to the arousal levels, execution and preparation of movements, the level of task performance, and reward. Therefore the PPN may serve as an integrative interface between the various signals required for performing purposive behaviors (Kobayashi et al., 2004). We postulate that the PPN facilitates, possibly via dopaminergic systems, the central processes for motor command generation and extrinsic sensory processing by modulating arousal and attentive states.

In non-human primate, limited lesions of the striatum induce deficits in rule acquisition (Divac 1972), cognition (Taylor et al., 1990), working memory performance (Goldman-Rakic, 1987) and selected attention (Battig et al., 1962). Laplane et al. (1984) reported a patient with restricted bilateral pallidal lesions who was appeared apathetic and unconcerned or attention deficits, and his affect was flattened and emotional responses were blunted in the absence of any motor disorder or pure psychic akinesia. These symptoms were also described in progressive supranuclear palsy (PSP) in which major lesions were observed in the subcortical areas including the PPN. Because loss of cholinergic PPN neurons were observed not only in PSP (75-80%) but also PD (43-57%) (Hirsch et al., 1987; Jellinger, 1988; Zweig et al., 1987, 1989), the loss of cholinergic PPN neurons in both diseases could attribute to attentive and cognitive impairments and sleep deficiencies in these diseases (Scarnati & Florio, 1997).

Both neuroanatomical (von Krosigk et al., 1992; Smith & Bolam, 1990) and electrophysiological (Häusser & Yung, 1994; Saitoh et al., 2004; Paladini et al., 1999) studies demonstrated that dopaminergic neurons, as well as cholinergic neurons, receive GABAergic inhibitory effects from the basal ganglia, particularly from the SNr. Consequently a BG-BS system appears to involve the interdigitation of motor information with information relating to reward and reinforcement by modulating the excitability of both dopaminergic and cholinergic systems.


*2.3. Clinical Procedure*

History, examination, and investigation were performed to ascertain the presence of certain preoperative factors. Preoperative digital radiographs using the parallel technique were taken with a cone indicator and reference marker placed on the radiographic sensor Written informed consent was obtained from the patients.

**Conventional re-root canal treatment:** Local anesthesia 1:80,000 lidocaine with epinephrine was administered and a rubber dam was used for isolation. Access to the root was gained by removing the coronal restoration, followed by application of GP solvent (Carvene, PREVESTDenPro Prevest Denpro Limited, Jammu, India) and 25 or 30 # H file (Mani, Utsunomiya, Tochigi, Japan) for the removal of radicular filling. Working length was established by 35 or 40 # K file (Mani, Tochigi, Japan). Canal cleaning and shaping was performed by modified crown-down technique along with copious irrigation by 3.0% sodium hypochlorite (CanalPro NaOCl, Coltène/Whaledent, Altstätten, St. Gallen, Altstätten, Switzerland). Calcium hydroxide (Metapaste, Meta Biomed, Cheongju-si, Chungcheongbuk-do, Korea) was used as an intracanal medicament in between appointments. Finally, obturation was performed by cold lateral condensation technique followed by composite coronal restoration.

All patients were recalled after 3 to 6 months for clinical and radiographic evaluation of the periapical healing after conventional re-root canal treatment. Periapical healing was observed in seven patients and five patients failed to appear on follow-up visit, therefore 12 patients were excluded from the study. Finally, 40 patients underwent periapical surgery due to nonhealing periapical lesions (Figure 1).

**Periapical Surgery:** To begin with, local anesthesia 1:80,000 lidocaine with epinephrine was administered and a full thickness mucoperiosteal flap was elevated. After identifying the lesion site, access to the lesion was achieved by performing window preparation in cortical bone with small round bur No. 2 (Mani, Tochigi, Japan) in a slow-speed handpiece (Figure 2). The periapical lesion was identified and surgically removed by a surgical curette (Hibro Int, Tokyo, Japan). Zirconia-coated ultrasonic tip (Pro ultra, Maillefer DENTSPLY, Ballaigues, Switzerland) was used for apicoectomy and retrograde cavity preparation (Figure 3). The 3 mm apical fragment of the root was resected perpendicular to the long axis of the root with minimum or no bevel. Finally, MTA (Pro-root MTA, DENTSPLY Tulsa Dental Specialties, Johnson city, TX, USA) was used for retrograde filling (Figure 4). The flap was then repositioned and sutured with a 3/0 silk suture (ETHICON, Johnson & Johnsons, New Brunswick, NJ, USA). A periapical radiograph was taken after surgery. Analgesics and antibiotics were prescribed. These patients were recalled after 12 months for a follow-up visit. Both clinical and radiographic examination was performed at each follow-up visit (Figure 5). The parameters studied for clinical examination were pain, swelling, sinus tract, tenderness to palpation, tenderness to percussion, mobility, and discoloration. Radiographic healing was assessed using Periapical Index (PAI). The radiographic interpretation was carried out by two blinded endodontists. The interexaminer reliability in evaluating the postoperative radiographs was calculated and presented.

**Figure 1.** Flowchart of Methodology.

**Figure 2.** A full-thickness mucoperiosteal flap was reflected and the window was created around the periapical area of teeth 11 and 21.

**Figure 3.** Retrograde cavity preparation was performed by zirconia-coated ultrasonic tip used for periapical surgery.

**Figure 4.** The retrograde filling was performed by MTA.


**1. Introduction**

Fatigue plays a vast role in all industries in terms of performance, safety, and productivity and is continually ranked among the top five human factors issues year after year [1]. It is estimated that fatigue costs more than \$18 billion per year in lost productivity alone, of which 84% is due to reduced performance at work, rather than absenteeism [2]. Fatigue in oil and gas operations specifically can have detrimental and catastrophic effects. An example is the BP Texas City Incident of 2005, which resulted in the deaths of 15 workers, 180 injuries, and a loss of at least \$1.5 billion [3]. Fatigue was identified as a contributing factor as some operators had been working 12-h shifts for as many as 29 consecutive days. Another major incident was the Piper Alpha oil platform disaster that resulted in the deaths of 167 workers [4]. It was determined that poor communication at the shift turnover was a contributing factor. Currently, due to the lack of consistent, sufficient, and effective incident reporting methods, it is difficult to estimate the extent to which fatigue has contributed to oil and gas extraction (OGE) incidents and injuries [5–7]. However, it is estimated that up to 80% of industrial accidents and incidents are due to human errors, for which fatigue was often partly responsible [5].

While the OGE sector is one of the most regulated sectors in terms of safety standards and regulations [8], fatalities in OGE are still alarmingly high, especially when compared to all other U.S. workers. The fatalities rate in this sector is about seven times greater [9]. This could be due

to the dynamic environment surrounding OGE operations, including high physical and mental workload, coupled with long work periods and shiftwork and prolonged social isolation [10]. The disproportionate fatality rate in this industry could be due to the complex combination and interaction of these factors contributing to high levels of fatigue. For example, OGE workers are typically working in remote locations for a 2–3 weeks' deployment and these locations are among the most demanding in terms of the technology used in daily operations and workforce demands [10]. Usually work schedules in OGE operations are 12-h periods in two shifts (day and night). While it has been established that 12-h shifts are not necessarily unfavorable, when they are coupled with long work weeks and night work, which are common practices in OGE operations, concomitant adverse events have been observed [11]. In addition to long work periods and shiftwork, OGE workers, especially drillers, are confronted with extreme cognitive demands. Drillers are responsible for the day-to-day operations on the rig. This includes monitoring and maintaining well control (i.e., to avoid blowout), organizing and leading work on the rig floor, as well as ensuring safety of the team [12]. Such high cognitive demands, paired with long work days and rotating schedules could potentially compound fatigue levels, thus increasing the risk of an adverse event.

Due to the multidimensional nature of fatigue, effective fatigue assessment is a critical challenge, particularly when considering the complex OGE working environment. While there is no gold standard for measuring comprehensive fatigue, several objective and subjective fatigue assessment methods exist that have been employed in different occupational sectors. The method for assessing fatigue is typically tailored to the environment and setting in which fatigue is being evaluated and can be considered as research-oriented (i.e., neuroimaging techniques and electrocardiogram) [13,14] and/or practice oriented in nature (i.e., performance test and subjective assessments) [15,16]. For example, within the transportation sector, there is an abundance of literature that demonstrates utility of different assessment methods to measure driver fatigue. Traditional lab-based studies have used methods that include brain activity via electroencephalography (EEG), eye movements using electrooculography, cardiovascular responses, biochemical markers, psychomotor tests, and subjective responses [17–19], while onboard devices exist that use EEG, which monitor and detect changes in drivers' states [20]. In the aviation sector, there is a trend of using performance tests such as the psychomotor vigilance test as a primary measure of fatigue rather than traditional lab-based methods [21], whereas subjective surveys are typically used within the healthcare industry [22,23].

A recent study employed real-time physiological monitoring in order to assess shiftwork in a 3-week offshore operation [24,25]. While valuable information was gained from physiological monitoring, the authors argued that this fatigue assessment approach was not sustainable or feasible for the OGE environment. Due to the hazardous and volatile environment of offshore operations, introducing sensors into this environment may create additional safety risks. This presents a challenge of identifying workers with high-risk fatigue levels. Without effective assessment methods, fatigue management practices that are targeted and effective in reducing fatigue-related incidents in the OGE industry are likely to be ineffective.

A potential safe and sustainable solution could be a non-intrusive, industry-specific subjective assessments tool for assessing fatigue in high-risk environments. Indeed, research within the OGE domain has traditionally assessed fatigue using subjective surveys and questionnaires [26–30]. However, the question remains whether these subjective research tools can be practically adopted in everyday OGE operations to assess worker fatigue. Mehta et al. [25] augmented physiological monitoring in their offshore shiftwork investigation with existing subjective methods to assess fatigue. The surveys included some of the more occupationally used fatigue scales, such as the Swedish Occupation Fatigue Inventory and the Occupational Fatigue Exhaustion Recovery [26–28]. They found that none of these surveys were comprehensive, relevant, and feasible for the OGE workforce. For example, compliance for completing these surveys declined over time due to the time-intensive nature of completing the surveys. On average, it took workers approximately 45 min to complete all the surveys used in this study. Additionally, the workers reported that some of the questions were not

clear and they had trouble understanding certain terms (e.g., some were unsure what "palpitations" meant). Because the SOFI was developed for the healthcare domain, the descriptions included medical terminology that nurses and caregivers are familiar with. As such, Mehta et al. [25] highlighted a critical gap in OGE fatigue assessment research and practice. Thus, feasible and sustainable fatigue assessment surveys need to be developed for the OGE sector that address user needs and education levels or utilize stakeholder feedback in OGE-specific hazardous work environment.

One methodology that holds strong potential to address tool development disconnect between research and practice is the Delphi consensus technique. The Delphi consensus technique is an iterative process that typically involves three to four rounds of questionnaires until consensus is reached regarding a specific topic. This technique has been employed successfully toward the development of human factors risk quantification in oil and gas drilling operations [31], fatigue surveys [32], as well as medical checklists used for safe surgical practices [33,34], and forecasting and issue identification, and framework development [35,36]. Since the Delphi consensus technique has been successfully applied in the OGE sector for human factors and in the use of other fatigue survey development, this technique provides a method that would be ideal for the development of an OGE specific fatigue survey.

The purpose of this study was to develop a comprehensive fatigue assessment tool specific for OGE operations utilizing the Delphi Consensus technique with participation from several OGE industry stakeholder groups, such as safety managers, consultants, researchers, and workers. To our knowledge, this was one of the first collaborations integrating user feedback from the OGE stakeholders and workers as well as occupational health and safety researchers. This effort will increase the likelihood that the new fatigue assessment tool will be adopted by the OGE industry, thus increasing its sustainability [37].

#### **2. Materials and Methods**

This study adopted a qualitative approach to develop a fatigue assessment inventory. A critical component in the development of this method was the integration of end user, i.e., OGE industry, inputs and expertise throughout the development process. This was completed in three phases. Phase 1 included a systematic gathering of existing fatigue survey based on predetermined criteria to develop a preliminary fatigue inventory. Phase 2 included the refinement of the inventory for content validation, conciseness, and relevance to OGE operations through industry stakeholders (i.e., safety managers from major OGE companies) and health and safety researchers (i.e., current doctoral students, post-doctoral researchers, and faculty from Department of Environmental and Occupational Health at Texas A&M University) using the Delphi consensus technique. Phase 3 involved further refinement of the inventory by OGE workers, who are the intended end-users. The inventory was refined for language and relevance to daily OGE work in this phase.

#### *2.1. Fatigue Inventory Development (Phase 1)*

Before the development of any assessment technique, the construct needs to be clearly defined and operationalized for the specific domain. In this study, fatigue in the OGE environment was operationally defined as a physiological state of reduced mental or physical performance capability resulting from sleep loss, disrupted circadian phase, and high workload (physical and mental). This definition was borrowed from the comprehensive definition of fatigue in aviation [38].

Potential items under consideration for developing the fatigue inventory were obtained from a systematic gathering of articles published from 1970 to 2016 and indexed in the Scopus database. Scopus was chosen for its thorough coverage of more than 22,800 titles with subject areas ranging from social sciences (psychology, economics, and business: 8698 titles), health sciences (100% MEDLINE, nursing, and dentistry: 7133 titles), physical sciences (chemistry, engineering, and physics: 7441 titles) and life sciences (neuroscience, pharmacology, and biology: 4601 articles). The criteria for inclusion was determined as: (1) ability to identify distinct fatigue symptoms, (2) applicability to health workforce, (3) sensitivity to a range of fatigue levels, and 4) English language. The search was completed in

April 2016. Search terms included: fatigue, physical demand, cognitive demand, psychosocial demand, stress, sleep, shiftwork, staff, adult, worker, employee, healthy, scale, assessment, and survey.

#### *2.2. Fatigue Inventory Refinement (Phases 2 and 3)*

Phase 2 included the refinement of the preliminary inventory for content validation, brevity, and relevance to OGE operations using two Delphi Consensus panels [39]. The size of Delphi panels varies widely. However, most studies using the Delphi Consensus method use panels of 15 to 35 people [40]. The Delphi consensus method used for this study was composed of 13 OGE stakeholders, with representation from researchers, consultants, and practitioners. Upon informed consent, the Delphi panel was presented with the preliminary fatigue inventory and instructed to exclude items based on the following criteria: (1) too general at describing a symptom of fatigue, (2) redundant of previous item, and (3) not relevant to OGE operation. Each item was vetted and discussed and then voted on whether to keep or remove the item. Items with a score of less than 80% consensus were removed. In Phase 3, focus groups were conducted with OGE workers, who are the intended end-user. OGE workers were provided with the refined inventory from the two Delphi consensus conducted in Phase 2. The inventory was further refined for language and relevance to OGE work.

#### *2.3. Participants*

Participants were recruited for Phases 2 and 3. Participant demographics are shown in Table 1. For Phase 2, OGE stakeholders, health and safety researchers and practitioners, were recruited to participate in the Delphi consensus study to refine the preliminary fatigue inventory. Industry stakeholders (from major energy companies based in Houston, TX; 61,000–75,000 employees) were invited for the Mary Kay O'Connor Process Safety Center at Texas A&M University. For Phase 3, one focus group was formed, with OGE workers across different job categories from a medium-sized (Houston, TX; 5000 employees) well-servicing company. Their role was to further refine inventory based on the language and relevance to OGE operations. Participants across both phases provided their informed consent approved through the Texas A&M Institutional Review Board (IRB2016-0676M).

**Table 1.** Participant Demographics.

#### **3. Results**

#### *3.1. Fatigue Inventory Development (Phase 1)*

Figure 1 illustrates the flowchart for number of articles identified in each of the steps described above. Ultimately, 14 peer-reviewed articles were included and reviewed, which yielded 12 widely used surveys, scales, or questionnaires (2 surveys were duplicated) [12,23,32,41–49]. This resulted in 230 question items. These questions were directly used with their accompanying instructions and scales in Phase 2.

**Figure 1.** Flowchart of articles gathered.

#### *3.2. Fatigue Inventory Refinement (Phase 2)*

This phase was completed in two steps utilizing two different Delphi Consensus panels. The first panel (Table 1) was provided the initial inventory, created in Phase 1. The panel was instructed to refine the inventory by improving grammar and language, and by eliminating redundant items. Two hundred and thirty items were discussed and the consensus technique led to a reduced 50-item inventory. Some examples of items that were removed due to vagueness of description included: (1) "*I feel tired*" (2) "*Thinking required effort*" and (3) "*I feel weak*," Another example for an item that was removed due to redundancy (e.g., "*My thoughts easily wonder*") was similar to a previous item (e.g., "*I have trouble concentrating*"). Items such as "*I don't do much during the day*" and "*I think I do a lot during the day*" were removed as the panel argued that truthful responses will be difficult to obtain as responders might be afraid to lose their job or human resources might interfere. An example of an item that was included after rewording the description was "*I use my days off recovering from work*" from the original "*I use a lot of my spare time recovering from work*". Another example was "*Vision is blurred*" was changed to "*Vision is blurred or distorted*." This was revised to combine two items on the preliminary inventory.

The panel was also required to reach consensus regarding how far the worker need to reflect (e.g., right now, past 24 h, or past week) to provide their responses on the fatigue symptoms. All panel members felt that a time frame (i.e., right now vs. previous week vs. three months ago) for the

instructions of the inventory needed to be established. A majority of the panelists stated that asking "*right now*" would not only reflect the most accurate symptom response from the worker, but also provide supervisors real-time valuable feedback from the workers necessary for implementing quick fatigue mitigation strategies (e.g., reallocation/rescheduling of personnel and work tasks).

In step 2, 5 OGE stakeholders refined the inventory for OGE relevance and/or utility of the responses on the items to guide management strategies. This reduced the inventory to 38 items. However, the panel added a question they felt was important regarding assessing cognitive fatigue. The added item was "*Fatigue interferes with my mental functioning*" which was developed from "*Fatigue interferes with my physical functioning.*" Two items were removed based on the panel's suggestion that responses would not be accurate due to the respondent being afraid of losing job or to the Human Resources tending to interfere. These items included "*I frequently dozed off during break period*" and "*I feel no desire to do anything*." Some examples of items removed due to redundancy included: (1) "*I can concentrate well*" and (2) "*Having tremors in limbs.*" This brought the total items to 39 items at the end of Phase 2.

The panel gave similar feedback about the importance of inventory instructions. The panel suggested that all items began with the same phrase of either "*To what extent...*" or "*To what degree* ... " but "*To what degree* ... " was favored. Additionally, a timeframe of "*right now*" or "*during the last shift*" was determined as the most critical and valuable for fatigue management.

#### *3.3. Fatigue Inventory Refinement Through OGE Worker Focus Group (Phase 3)*

Eleven OGE workers refined the inventory for OGE relevance and language. In this phase, all 39 items were kept. Feedback from the focus group was used to reword questions for better comprehension, which is expected to allow workers to accurately respond to questions. The workers agreed that all 39 items were relevant to OGE operations. However, they suggested that a few items be reworded. For example, the item "*To what degree do your joints (e.g., knee or elbow) feel achy?*" was changed to "*To what extent do your joints (e.g., knee or elbow) feel stiff or achy?*" Another example included changing the item "*To what degree do you experience tense muscles?*" to "*To what extent do you experience stiff muscles?*"

Additionally, workers gave their input on the type of scale they would prefer to respond to (i.e., 1 (*none*) to 7 (*a lot*) vs. 0 (*Not at all*)-10 (*Extremely*)). Of the 11 workers, 9 preferred the 0 (*not at all*) to 10 (*extremely*), and the other two did not have any comments regarding the response scale. A majority of the workers stated that it was natural for them to perceive zero as "*nothing*" or "*not at all*", while 1 meant a little bit or slightly more than zero. Additionally, workers expressed that they preferred "*to what extent* ... " rather than "*to what degree* ... ". The workers also suggested that having a Spanish version of the final inventory would be critical for implementation and translation to sustainable practice. Over 50% of workers spoke Spanish as their first language. They expressed that while they understood the English version, it would be easier for them to understand and respond accurately and quickly with a translated inventory.

#### *3.4. Final Fatigue Inventory (FRAME)*

After health and safety researchers, OGE stakeholders, and OGE workers reviewed the preliminary inventory of 230 items, the final inventory decreased to 39 items. The 39 items were further reviewed by the study research team to verify that all dimensions of fatigue (e.g., physical, mental, sleep, and shift-related) were represented. In this review, the research team identified 13 items that would not offer sufficient value to the organization (e.g., supervisors, safety managers, etc.) for implementing effective fatigue management practices, but that could provide a better understanding of workers' personal strategies to manage fatigue. Because the original purpose of the fatigue inventory was to help organizations develop effective and sustainable fatigue mitigation strategies, these items were removed to enhance ease of use of the new tool. Examples of the removed items included: (1) "*To what extent do you worry about issues at home making it hard to relax?*" (2) "*To what extent do you use alcohol*

*to help you sleep?*" (3) "*To what extent are you concerned for how long you can keep going at your work?*" and (4) "*To what extent would you work overtime or an extra shift when you are sleepy or fatigue in you needed extra money?*" It should be noted that the mentioned items were discussed extensively in Phase 1 and Phase 2. Participants from both the Delphi Panels and Employee focus groups suggested that these were interesting items and hence were ultimately kept in the inventory, but unsure how responses could be used for fatigue management programs. Ultimately, 26 items were selected for final fatigue inventory (Figure 2). Figure 2 also lists the number of items that were classified within each dimension of fatigue (physical, mental, sleep or shift-related) in each phase. It should be noted that items can be classified as more than one dimension. An example of this is the item "*fatigue interferes with carrying out certain duties and responsibilities.*" This item could be classified as all four dimensions.

**Figure 2.** Summary of Inventory Item Reduction.

The final fatigue inventory recommended by the research team along with when the question should be asked (pre-shift or post-shift) is shown in Table 2.

**Table 2.** Final Fatigue Inventory Questions.

#### **4. Discussion**

The aim of this study was to develop a comprehensive fatigue assessment inventory specific for OGE operations through involvement of OGE stakeholder input. The resulting survey instrument, named Fatigue Risk Assessment for high-Risk Environments (FRAME) survey has a total of 26 items encompassing four dimensions of fatigue. It should be noted that this survey was developed by obtaining input from the OGE industry, and as such its application to other high risk industries, such as mining, need to be evaluated.

A recent study comparing objective and subjective fatigue assessment in offshore work used five different surveys to capture comprehensive operator fatigue over the course of a hitch [25]. An average worker needs approximately 45 min to complete all the surveys as the wordings were not clear difficult to understand. As a result, compliance was low as time progress over the hitch. Moreover, lengthy surveys are at risk of resulting in participant response fatigue, implying that questions asked later in a long survey are typically prone to increased error and untruthful and unreliable responses [50]. Pilot studies have found the FRAME survey, developed here, takes no longer than 10 min to complete, simply due to the reduced number of times [51]. This would allow for compliance to be greater and additionally recovery time between shifts, as operators will not spend a great amount of time completing surveys. Sustained use of the FRAME survey could help to facilitate the successful implementation of effective fatigue management practices outline in the API Recommended Practice 755: Fatigue Risk Management System [52].

Fatigue-related incidents have been continually identified as one of the most dangerous risk factors in high-risk industrial setting [27]. When workers were asked to define fatigue, most simply said it's when they are "tired" or "exhausted". Fatigue is typically described as tiredness, overexertion and strenuous movements [27]. Overexertion injuries were the third leading cause for days away from work in 2007 behind being struck by an object or caught in object, equipment, or material [53]. Currently, the most common method for assessing physical fatigue in OGE sector is surveys and questionnaires [26,29,30,54]. Regarding physical workload, the FRAME survey has 10 items to gauge physical fatigue, ensuring that this important dimension of fatigue is assessed through the new tool.

Not only does physical workload affect fatigue-related performance and safety outcomes, intense mental workload associated in specific operations, specifically drilling and well control scenarios, can contribute significantly to fatigue development. In both onshore and offshore operations alike, drillers are responsible for maintaining and ensuring rig safety, in addition to performing day-to-day tasks required for rig performance. The day-to-day tasks are outlined by a well operation plan [55]. The well operation plan is an overview of the drilling parameters that must be monitored and maintained. In addition to following the well operation plan, drillers are also responsible for providing well control if necessary. This means that in the case of an adverse event such as a kick or loss of circulation, they are required to intervene to avoid blowout [55]. Performance on daily operations relies heavily on cognitive dexterity [12]. Similar to physical fatigue assessments, the most common method that is currently used to assessing cognitive fatigue in OGE is surveys and questionnaires such as the Swedish Occupational Fatigue Inventory and Work Ability Index [26–28]. However, none of these surveys were designed specifically use for OGE operation. Since the FRAME survey was developed with OGE input and consideration, it is better suited than current surveys being used for cognitive fatigue assessment. To assess cognitive fatigue, the FRAME survey has 12 items. It might be argued that workers may tend to respond to some questions based on their awareness rather than their experience (for e.g., question item 18 in Table 2). Future testing (such as reliability analysis) may help identify questions whose responses could potentially be biased by awareness rather than actual experiences.

In OGE operations, insufficient sleep and changing shift pattern are the primary cause of fatigue [11]. Traditional work schedules are typically 7–14-day tour, with sequential 12-h shifts and shift changes. Evidence suggests that 12-h shift are not necessarily detrimental, but when coupled with extended workdays (i.e., beyond 4 days) and/or night work, there are many adverse effects on worker performance, safety and health [11]. As sleep and shift-related factors are a common source of fatigue, the FRAME survey has nine items to effectively assess these factors. A common practice in OGE operations is the use of a swing shift (i.e., switching from a night shift to a day shift or from a day to night shift). Swing shifts are used to allow workers to become adapted to day schedule for them to return home after a hitch [56]. It has been observed that workers can physiologically adapt to 12-h night shift but their internal circadian cycle is desynchronized for at least the first 4-5 days [57]. But those who start with a day-shift then switch to night shift do not adequately adapt [57]. The common practice of switching shifts in the middle of a hitch could potentially introduce several health and safety. The responses from sleep and shift-related questions could help to test effectiveness or implications of a swing shift. In addition to understanding the implications of swing swifts, responses on the shift and sleep-related questions could explain or allow for better interpretation of other responses for other questions within the FRAME survey. For example, if a worker has reported a low score (i.e., did not recover between shifts) to the item "*To what extent did you recover completely between shifts*", it should be taken into account if they report a high score (i.e., found it extremely difficult to pay attention) to the item "*To what extent did you find it difficult to pay attention to someone, even when being spoken to directly."* By understanding the cause and consequence of fatigue, effective mitigation strategies can be designed, which ultimately may reduce fatigue-related injuries and incidents.

Valuable feedback has been received from employee focus groups regarding the survey content. It was suggested that a Spanish version of the FRAME survey would be highly beneficial. According to the BLS, 32.3% of workers within extraction are Hispanic or Latino, while the cross-industry average is merely 16.1% [58]. In 2011, 25% of OGE worker fatalities were Hispanic or Latino [53]. In addition to NIOSH identifying *"decrease-fatigue related injuries and fatalities in the oil and gas extraction industry"* as a top strategic goal for the Oil and Gas Extraction Program, *"reduce the incidence of injuries, illnesses, and fatalities among vulnerable workers in the oil and gas extraction industry such as contract workers, young and old workers, workers new to the industry, and immigrants"* has also been determined as a strategic goal. The addition of a Spanish version will allow for a greater number of workers to be properly assessed. However, future research would be needed to assess the readability of the FRAME survey with Spanish-speaking workers.

There are a few limitations that should be mentioned. First, the employee focus group was completed using only one onshore well-servicing company. However, the second Delphi Consensus Panel was composed of representatives from major energy companies. By using both small and major companies, considerations from different size companies were incorporated in the development of the FRAME survey. While subjective assessments only provide workers' perception of their fatigue, due to the dynamic working environment of OGE operations, an industry-specific survey that is feasible, sustainable, and non-intrusive appears to be a viable approach to improving our understanding of fatigue. However, objective assessments beyond physiological measures need to be explored for OGE operations. Future research is required to test the reliability and validity of the FRAME survey in onshore and offshore OGE operations against traditional fatigue assessment methods such as performance tests and physiological monitoring. In addition to testing the reliability and validity of the FRAME survey, the scoring method should also be evaluated. A potential scoring method could be to sum the response for each dimension individually. The sum score of each dimension may identify what aspect of fatigue the workers are at the greatest risk, which could help to identify mitigation practices. Finally, while the FRAME survey provides worker perceptions on the degree to which fatigue impacts their physical and cognitive capabilities, future work could investigate coupling the survey with quantifiable fatigue sources (e.g., weather, rig activity—that implicates physical and cognitive workload, shift lengths/durations) to provide better decision support to supervisors and schedulers for effective and guided fatigue management practices. It is possible that, while the Delphi panel added question items, the panel members were biased by the nature of questions in the existing surveys—which were largely focused on identifying and quantifying symptoms rather than identifying the role of work factors.