In this paper, a perspective on the application of Spatially- and Angle-Resolved PhotoEmission Spectroscopy (ARPES) for the study of two-dimensional (2D) materials is presented. ARPES allows the direct measurement of the electronic band structure of materials generating extremely useful insights into their electronic properties. The possibility to apply this technique to 2D materials is of paramount importance because these ultrathin layers are considered fundamental for future electronic, photonic and spintronic devices. In this review an overview of the technical aspects of spatially localized ARPES is given along with a description of the most advanced setups for laboratory and synchrotron-based equipment. This technique is sensitive to the lateral dimensions of the sample. Therefore, a discussion on the preparation methods of 2D material is presented. Some of the most interesting results obtained by ARPES are reported in three sections including: graphene, transition metal dichalcogenides (TMDCs) and 2D heterostructures. Graphene has played a key role in ARPES studies because it inspired the use of this technique with other 2D materials. TMDCs are presented for their peculiar transport, optical and spin properties. Finally, the section featuring heterostructures highlights a future direction for research into 2D material structures. The field of two-dimensional 2D) material research began with the discovery of graphene in 2004 ,2, whichD materiaThe family of 2D materials covers the complete range of electrical proprieties from superconducting to insulating ,4,5,6. AIn this review the preparation methods employed to produce 2D material are discussed briefly, and include Chemical Vapor Deposition (CVD) , PhysicaAn ideal experiment to study the band structure of 2D materials should allow the visualization of the sample in the macro or nanoscale, utilizing a small portion of sample material to obtain ARPES. In the past few years, instrument advances have been made that allow complex measurement operations to be performed at synchrotron light facilities and using laboratory-based equipment. In this review, the operating principles of the spatially localized ARPES systems will be presented. First, an overview of early ARPES measurement setups will be discussed before describing state-of-the-art, spatially resolved ARPES equipment. 2 [2, VSe2 [2 [This paper features some of the most interesting results obtained to date on graphene, transition metal dichalcogenides (TMDCs), and 2D heterostructures along with discussions about future instrument upgrades for spatially-, spin-, and time-resolved acquisitions. Graphene was a starting point for the investigation by spatially localized ARPES of 2D materials, an example of advanced spatially localized investigations on polycrystalline few layer graphene has been reported . TMDCs h2 , and pot[2, VSe2 , and ReS VSe2 [2 ,12 are a VSe2 [2  but case VSe2 [2 ,15 as we VSe2 [2 ,15 have The ARPES technique needs an instrument setup that allows (i) the possibility to investigate the photoemission intensity as function of emission angle and (ii) the ability to distinguish the kinetic energy of the photoelectrons. A sample for ARPES must be crystalline to possess an ordered band structure, and its surface must be smooth to conserve the k-parallel component from the crystal to the vacuum . The surIn the very first ARPES experiments, the samples were a few millimeters wide and photoelectrons were detected using a hemispherical analyzer with a small acceptance angle and a simple electron counting detector. The role of the electron analyzer is very important; indeed, it is the element that allows one to measure the photoelectron kinetic energy, creating, with the simplest 1D detector, an intensity versus kinetic energy spectrum b. In theWith 1D detector mapping the acquisition of a full band structure was time-consuming and needed complex sample movements. The introduction of 2D electron detectors provided the means to reduce the number of sample rotations, as illustrated in A recent enhancement to these analyzer systems has enabled angular scans to be made in two dimensions in k-space without tilting or rotating the sample. The scanning of k-space is carried out electronically using dedicated deflectors. An example representation of the region of k-space that can be sampled with these detectors is represented by the orange shaded area in setups that present extremely small light spots, and where surface mapping is done by moving the sample with respect to the light;setups that allow visualization of the real and k-space by extracting electrons using strong electric fields.Considering the complex procedure needed to perform conventional ARPES from large area samples, it is understandable that to perform ARPES on micro- or nano-sized samples poses a significant technical challenge. Instruments need to scan a vast region of the sample surface in real space (X/Y plane) to find the interesting regions, typically microns wide, and then perform ARPES on them. Nowadays there are different setups available to research and industry to be able to do spatially localized ARPES, and the instrument configurations can be divided into the following two categories:For the first category, the spatially-localized ARPES is typically carried out at synchrotron light source facilities, see With these setups it is possible to visualize samples in real space by mounting them on motorized stages  and collARPES mapping is acquired either by moving the electron analyzer in UHV over a range of different emission angles, which is the configuration used at the Spectromicroscopy beamline in the Elettra synchrotron , or, mosThe synchrotron light source is important not only for the brilliance of the light, but also because it can allow ARPES to be performed at different photon energies and polarizations. Moreover, the broad range of photon energies available allows X-ray photoemission spectroscopy (XPS) to be performed. The ability to perform spatially localized core-level spectroscopy gives a much deeper insight into surface conditions such as composition, oxidation and contamination.For the second category, the photoelectrons are accelerated by an extractor electrode towards an electron optical column, which contains electrostatic or magnetic electron lenses, corrector elements such as stigmators and deflectors, apertures placed in the image plane and contrast apertures. Such instruments are usually referred to as PhotoEmission Electron Microscopes (PEEMs), see in These instruments allow the sample to be imaged without moving it either in real or reciprocal space c,d. ThisHowever, a PEEM column cannot filter the photoelectron kinetic energy, therefore it is missing an ARPES measurement requirement. To distinguish the kinetic energy of photoelectrons, PEEMs must be equipped with energy filters that allow one to scan the photoelectron kinetic energy spectrum, these more complex setups are called energy-filtered PEEM (EF-PEEM). The ARPES mapping operation is acquired by imaging at a range of kinetic energies of the full-wavevector landscape d, allowiIncluded among the available commercial EF-PEEM instruments are the NanoESCA II and the Time-of-flight (TOF) PEEM of Focus , the METIS and FE-LEEM (low energy electron microscopy)/PEEM P90 of SPECS , and the ELMITEC PEEM/LEEM . The energy selection in these instruments is performed in a range of different ways, including using hemispherical analyzer(s), TOF filters and electrostatic/magnetic retarding optics.The best energy resolutions are obtained by the hemispherical analyzers and TOF, for example NanoESCA II is equipped with two hemispherical analyzers coupled in a “S” fashion to minimize the aberrations , and witAll these instruments have a lateral resolution in the nanometer range, LEEMs in this respect typically out-perform PEEMs, but in any case, spatially localized ARPES is usually performed over an area of a few microns and limited by the fact that the area is selected by means of a mechanical aperture.z dispersion, but it is a limitation for 3D materials where synchrotron tunable radiation must be employed to analyze the kz dispersion. Indeed, several EF-PEEM are installed on synchrotron light source facilities to offer the combination of high flux and versatility of synchrotron light with the fast imaging and stability of the PEEM. Almost all the synchrotron light facilities host a PEEM beamline, among those facilities there are NanoESCA [Laboratory-based equipment typically use discharge lamps, such as a He lamp that offers 21.2 eV (He I) or 40.8 eV (He II) photon energies. The poor photon tunability does not represent a problem for single layer 2D materials because they do not have a kNanoESCA  and NanoIt is important to note that using a technique called dark-field PEEM a portion in k-space and energy can be selected ; this deThe next section is principally focused on spatially localized band structure measurements nonetheless other types of ARPES setups are included in the context of some of the most representative 2D materials. Each type of ARPES setup presents its own pros and cons which are reported in Epitaxial growth by CVD or PVD. This method allows flat and azimuthally oriented layers to be deposited on large single crystal substrates. It is easy to control the number of layers by changing the deposition time, growth chambers can be directly mounted onto ARPES equipment so that samples can be transferred for analysis under UHV conditions. With epitaxial films it is not necessary to employ spatially-resolved ARPES to limit the analyses region on single material grains because the grains are azimuthally oriented with the substrate and form a macroscopic continuous ordered crystalline lattice. Because of the large amount of signal available for ARPES, advanced analyses such as spin-resolved or time-resolved ARPES are feasible on such samples  ,33 and RThe properties of graphene in contact with different species such as substrates, intercalating agents, and deposited species, can be studied by ARPES. For example graphene intercalated with weakly interactive metals or oxygen can remove hybridization with the substrate ,36,38,41The studies on spatially localized ARPES on graphene have been fundamental for the investigation of azimuthally disordered CVD-grown graphene. This analysis has been carried out with graphene on copper ,50,51,52One important study that emphasizes the power of spatially-localized ARPES for graphene was carried out with multi-layer graphene on copper ; some of//, in all the desired directions. For example, the spectra in The example study reported in Important spatially localized ARPES studies have been acquired on mechanically exfoliated graphene flakes , on bi-lAll these studies that focused on graphene demonstrate a methodology that can be applied to the study of other 2D materials, confirming the pivotal role that graphene had as the prototype 2D material. h-BN), the analogue of graphene with boron and nitrogen atoms, has been synthesized and studied in a similar fashion to graphene. It is an insulator with a band gap of more than 5 eV [Hexagonal boron nitride  deposition of alkaline metals followed by ARPES and (ii) time resolved pump and probe ARPES.2 [As stated above for graphene, doping the surface by deposition of alkaline metals it is a well-known method to shift the Fermi energy of the material and, in the case of semiconducting TMDCs, allows analysis of the CBM ,91,92,932 . In the 2  are rare2 [Another way to study the conduction band of the sample is time-resolved ARPES involving “pump and probe” experiments. In these experiments, two photons with a femtosecond delay are sent to the sample. A photon source called “pump” has the function to excite electrons into the conduction band, while the other source called “probe” has the role of extracting photoelectrons. This technique is used to reveal the dynamics of the charge carriers and it is the only method that is able to visualize the electron relaxation path in excited states with momentum resolution . Similar2 ,99, beca2  and TOF 2 ,102. It 2 and VSe2, are metallic. They have a 1T stacking and show low temperature transitions to states with charge density waves (CDW) leading to periodic modulations of the electronic charge density. The resulting superlattices can be either commensurate or incommensurate and the CDW ordering can compete with other phenomena such as superconductivity and anti-ferromagnetism. ARPES investigation of these materials is still at an early stage, these materials have been only analyzed by ARPES in their bulk form [Other TMDCs, such as TiSeulk form ,104 or aulk form ,105.2 and VSe2 small bulk crystals. The CDW effects in TiSe2 are visible in the acquisitions along the Γ→M direction; the replica of the photoemission features in Γ, due to the Se 4p orbitals, is visible in 2 are much more subtle and they are still under investigation [tigation . Their v2 for its unusual in-plane anisotropy. The ReS2 structure is considered a distorted 1T crystal structure and when compared to the 2H structure of group VIB TMDCs, an additional valence electron leads to the formation of Re chains along the b-axis of the crystal, see scheme in 2 single and bi-layers. While z dispersion. From the full-wavevector ARPES reported in 2 has not been clearly established and further studies will have to be carried out to fully understand this material.A recently studied TMDC is ReS2 [2 [2 [2 [2 and MoS2 were performed by micro acquisition on exfoliated flakes [2 and MoS2 can now be grown epitaxially and advanced ARPES methods such as surface doping [The current state of knowledge from ARPES of materials such as TiSe2 , VSe2 [12 [2 ,104, ReS2 [2 [2 ,12,106, [2 [2 [2  may be rd flakes ,107,108.e doping ,93, spine doping  and timee doping ,99 can b2 compared to the more prevalent use of SiOx which confirms the extreme sensitivity of 2D layers to the underlying substrate [2, WSe2 and MoS2, where the band structure has been studied by micro-ARPES [2 has been carried out by micro-ARPES; the band structure changes as a function of the angle between the layers and a remarkable dependence of the angle with the electron effective mass and of the position of the bands has been found [As reported above, by mechanical transfer it is possible to place samples on an arbitrary substrate and understand how their properties are modified by contact with other species. An example of this is the micro-ARPES study on suspended MoSubstrate . Examplero-ARPES ,112,113.h-BN and semiconducting TMDCs as well as phosphorene; these could be the components of future ultrathin devices utilizing exclusively 2D materials [Two-dimensional heterostructures are a vibrant research field with the principal aim of creating novel ultra-thin devices with unprecedented properties achieved by combining different 2D materials . So far aterials .2 [2 [2 [2 [2 [As reported above for the isolated 2D materials, some 2D heterostructures have also been synthesized by epitaxial methods, the advantage of this growth method is the possibility to perform complex ARPES analysis, but they are even more complex to synthesize than the isolated 2D materials. Several epitaxial routes are based on the use of graphene because it is so well-studied that advanced growth on top of it are possible, for example, TMDCs are deposited onto graphene by CVD or PVD. Epitaxial graphene on SiC represents an excellent example of graphene used as a basis for the growth of other 2D materials such as TMDCs: WSe2 , MoS2 [92 [2 , MoSe2 [2 [2 [2 , and 2D 2 [2 [2 ,116. The2 [2 [2 . Epitaxi2 [2 [2 ,118,119.2 [2 [2  and GaSe2 [2 [2 . The lat[2 [2 [2  and WSe2[2 [2 [2  showing [2 [2 [2 .One way to overcome the disadvantage of complex CVD and PVD deposition methods to form heterostructures is the mechanical transfer methods, as mentioned above, which lends itself to spatially localized ARPES. For transferred layers, one of the most studied components for heterostructures is graphene or graphite. Indeed, graphenic flakes are now used as a conductive substrate ,15 and ah-BN were the first to be studied, because it was clear that the properties of graphene were strongly influenced by the substrate. Hexagonal boron nitride being a flat, insulating material, with a dangling bond-free platform was a perfect candidate to study graphene pristine properties [The 2D heterostructures formed by mechanical exfoliation have been extensively used for the study of the electrical, magnetic and carrier transport properties of 2D materials ,127,128.operties . Spatialoperties .2 [Graphene has been coupled with several TMDCs, a lot of studies have been focused on MoS2 ,131,132 2 have been focused on studies of band offsets [2 is reported. In this experiment the azimuthal disorder of transferred graphene made it possible to have on a single substrate several different alignments between the MoS2 and graphene. By using spatially-localized ARPES enabled the study of individual flakes and therefore made it possible to establish the band structure of the heterostructure as function of the layer orientation [2 with the character of the bands for the Mo 5d and S 3p orbitals is presented. 2, and for positive wavenumber graphene with Γ→K direction aligned with the direction Γ→K of MoS2. In the graphene π band there are clearly detectable gaps opening when crosses a MoS2 feature with an out-of-plane character. For example the gap “1” is due to Mo 5dz2 bands and it is visible only when the 2D materials are not aligned, while the gap “2” is visible in any of the two flakes reported in pz orbitals [2/graphite [2 and MoS2/graphene [2/graphene it has not [The studies of heterostructures composed of graphene and MoS offsets ,131, min offsets . A strongraphite , MoSe2 agraphene ,131 it h has not , so a mo2/h-BN [Few examples exist in the literature that report spatially localized ARPES on heterostructures that do not contain graphene, one recent example is the heterostructure WS2/h-BN . This co2/h-BN .2/WSe2, both single layers, and has been studied by micro-ARPES. An optical microscope image of the sample is shown in 2 bi-layer. The observations showing that the valence band edge remains at the K point and that the band alignment is type II are both extremely important for electronic and optoelectronic applications [The only example in the spatially-localized ARPES literature reported so far of all-TMDC heterostructures created by mechanical exfoliation has been reported in Ref. ; the maiications .Complex heterostructures will become increasingly available for spatially localized ARPES studies because of the advances in the mechanical transfer technology used to form complex 2D devices for optical, carrier transport, magnetic, and spin property characterization ,136,137.In this review, the principles of spatially-localized ARPES have been reported. Experimental measurement configurations, from early ARPES systems to the most advanced state-of-the-art instruments for micro and nano-ARPES have been presented. The technical challenges of using these tools have been discussed and both synchrotron and laboratory-based instruments have been introduced.z, which is particularly useful for bulk crystals [ARPES using laboratory-based equipment is feasible with crystal domains a few microns across, the light intensity available is typically lower than those at synchrotron facilities, but long acquisitions are possible because longer measurement times can be made. Also, they are very stable instruments that are not affected by beam oscillation or downtime. Laboratory-based instruments can also be extremely useful for evaluating new sample materials and for performing preliminary analyses prior to accessing synchrotron beamtime. Spatially localized ARPES synchrotron beamlines allow the exploration of the band dispersion in kcrystals ,85, and crystals . Further// profiles in arbitrary directions as is done in In this context the reported examples in Examples of graphene, TMDCs and 2D heterostructures experiments have been used to showcase the potential of spatially-localized ARPES for 2D material investigations. Because spatially-localized ARPES is directly linked to the lateral dimensions of the material, the preparation methods for ultra-thin layers has been discussed, highlighting how mechanical exfoliation and transferred films represent the most promising methods for micro-ARPES characterizations.Graphene has been discussed in detail because it is the prototype 2D layer and the model material to which spatially localized ARPES has been applied. ARPES on graphene allows one to visualize directly the Dirac cones, which are characteristics of its semi-metallic structure, probing its doping level , interacTMDCs have been studied for their novel optical, electron carrier transport and spin properties. Spatially-localized ARPES has been used to observe the changes in the band structure as function of the number of layers, as illustrated in The field of 2D heterostructures is probably the most interesting subject for spatially-localized ARPES. In this review are reported several heterostructures based on graphene which itself can be used as a conductive substrate ,15, a prTo date, the analyses by spatially-localized ARPES have been used for only a few kinds of 2D heterostructures, and rarely have been made solely from TMDCs . HoweverThe possibility to observe the band structure in a confined space created by the overlapping of microscopic 2D sheets will allow the study of a whole range of phenomena from band alignments to many-body effects and soon also spin polarization and carrier dynamics. The prospects are very good for the spatially resolved ARPES technique to revolutionize the way in which promising 2D materials and heterostructures are studied and analyzed.


The valgus-impacted (VI) 4-part fractures are a subset of fractures of the proximal humerus with a unique anatomic configuration characterized by a relatively lower incidence of avascular necrosis after operative intervention.The present study reports the midterm clinical and radiological results of a large series of consecutive patients with 4-part VI fractures treated with a minimal invasive technique of internal fixation.Over a ten-year period (2004-2014), we treated 56 patients with a true 4-part valgus impacted fracture of the proximal part of the humerus. Four patients were lost to follow-up and three died, leaving 49 patients  available for the study. Fracture fixation was achieved through the lateral transdeltoid approach with transosseous suturing of the tuberosities to each other, to the metaphysis and to the articular part of the humeral head avoiding gross disimpaction of the humeral head from the valgus position. Functional outcome assessment was performed using the parameters of the Constant-Murley score within a mean follow up period of 43,8 months .All fractures were united within the first 3 months except one that showed late displacement and finally nonunion. The median Constant score was 81,7 points and the functional score in comparison with the unaffected shoulder was 86.2%. There were three patients with total Avascular Necrosis (AVN) of the head revised to hemiarthroplasty. The nonunion case was revised to reverse shoulder arthroplasty 12 months after surgery. In five cases, absorption of the greater tuberosity was noted in the last radiographic control without any serious consequences to the shoulder function.Advantages of this minimally invasive technique can be summarized as shorter operative time, no use of hardware, minimal soft tissue damage, low incidence of avascular necrosis, stable osteosynthesis with “tension band effect” and adequate rotator cuff repair allowing for early joint motion. The AO/OTA classification in contrast contains the 4-part VI fracture in the subgroup 11-C1.1 (slight displacement) and 11-C2.1 (marked displacement) . Robinsoet al. [Treatment options for this unique fracture range from non-operative care to internal fixation and shoulder arthroplasty. Court Brown et al.  reportedet al. , 5.et al. [Locking plates represent a significant advancement in the treatment of these injuries as they can provide more secure fixation in osteoporotic fractures, but recent systematic reviews have shown very high rate of complications  , 7. Broret al.  recommenet al. .et al [Several other authors -17 have et al  reportedThe present study reports the midterm clinical and radiological results of a large series of consecutive patients with 4-part VI fractures treated with a minimal invasive technique of internal fixation.2During a ten-year period (2004-2014), a consecutive series of 427 patients underwent surgical treatment for displaced fractures of the proximal humerus in our Department. Internal fixation with transosseous sutures was applied in 138 patients; 56 of them had sustained a true 4-part valgus-impacted fracture. Eligible for inclusion into the study were considered those patients who were medically fit to receive general anesthesia and mentally alert to cooperate with the prolonged rehabilitation protocol. Written informed consent was obtained by all participants for prospective data collection, follow up exams and publication of the clinical and radiological results in international journals. Ethical approval was not necessary, according to our committee, for this type of follow up study as the same established and already published surgical treatment was applied to all patients.1). The radiological criteria for considering a fracture as amenable to osteosuture fixation were: a) loss of posteromedial hinge integrity, either medially or laterally, no greater than 10 mm, b) valgus impaction angle up to 45 degrees, c) displacement or angulation of the greater tuberosity by > 5 mm or 45 degrees in respect and finally d) presence of adequate metaphyseal head extension by minimum 10 mm.All patients had sustained a fresh or not older than one month, fracture of the proximal humerus with true valgus impaction: the later was defined as the angle between the fracture plane of the articular segment and the axis of the humeral shaft and was accurately measured together with the length of posteromedial hinge, in the initial anteroposterior radiograph in zero rotation; additional CT-scan images were obtained when it was necessary . Thirty-six patients sustained a fracture upon a standing or lower height fall, 2 upon falling from heights > 2m and 11 after involving in a motor vehicle accident. Associated injuries were present in seven patients (14.2%) while four patients had sustained old injuries  and were referred to our Department by other hospitals. The right shoulder was affected in 32 cases and the left in 17. There were no clinically detectable neurovascular deficits preoperatively. Thirty-six patients had been regularly employed prior to the injury: twenty-two had a sedentary job, and fourteen performed manual work.Four patients were lost to follow-up and three died from causes unrelated to the fracture, leaving 49 patients for follow up evaluation. There were 33 women and 16 men with an average age of 60,1 years  at the time of injury  and tied up not only the tuberosities to each other but also to the articular fragment and to the medial and lateral side of the diaphysis, in a “tension band manner” . The surgical technique of fixation and the sequence of suture passing and knot tying have been previously published by the senior authors [Under general anesthesia the patient was placed in the “beach-chair” position with at least 70 authors , 20. Sta2.2nd postoperative day until the 2th-3th postoperative week. The second phase included passive assisted exercises in the supine position as the patient was trying to reach the bed, supporting his injured shoulder by the healthy arm or special designed sticks. Until the 7th-8th postoperative week, forward elevation and external rotation were performed in the supine position while internal rotation in the standing one with the aid of sticks. As the union progress was completed, active exercises using gradually increased weights (starting from 1 kilo) were administered until the 12th postoperative week. If the patient was capable to forward elevate 2-3 kilos in the supine position, active dynamic shoulder motion and strengthening exercises were administered in the standing position until the 6th postoperative month. Preservation of shoulder motion and strength was maintained for another 3 to 4 months. The patient was seen every two weeks for the first two postoperative months and was instructed and guided by us. We believe that a simple prescription of physiotherapy does not help the patient as much as this close and monitoring consultation with his surgeon.A closely monitored 3-phase rehabilitation program was given to all patients initially consisted of pendulum exercises starting on the 22.3All patients were prospectively monitored for intraoperative and postoperative complications. The functional outcome was independently assessed at the third, sixth and twelfth postoperative month as well as at the last follow up using the parameters of Constant-Murley score. The average period of follow-up was 43.8 months . Some patients missed one or more follow-up appointments, but all returned for the 2-year follow up visit when we also assessed the work status of those patients who had been regularly employed prior to the injury.o  and the average loss of posteromedial hinge integrity 1,29 mm (range 0-7 mm). Twenty-two patients (44.9%) had an intact hinge (0 mm of displacement), whereas the majority of the rest 27 patients (68%) showed medial displacement of the shaft in respect to the humeral head fragment.Standardized “trauma series” of the shoulder were ordered at presentation and at each of the follow-up appointments. We measured the impaction angle, the degree of posteromedial hinge disruption and the displacement or angulation of the greater tuberosity in the initial radiographs using the tools in the PACS system of our hospital. Progress of fracture union, loss of reduction, nonunion, residual tuberosities displacement and evidence of partial or total AVN or early osteoarthritis were assessed at each radiographic follow up control. All radiographs were measured by the senior one of us (A.P.) and by a Professor in Orthopaedics (M.T.) who was independent of the project. The mean preoperative impaction angle of the humeral head was 43,793The mean duration of surgery was 71 minutes  and the average duration of hospital stay 3 days (range 2 to 5 days). The time from injury to surgery for the fresh fractures was ranged between one and four days. No intraoperative or early postoperative complications and cases of superficial or deep infection were noted. No postoperative neurovascular compromises were detected also.3.1o (160-180o), the average external rotation between 50o and 80o and the mean internal rotation with respect to the posterior spine segment reached by the thumb at least the T9 to T8. All patients were quite satisfied with the result, having no pain with vigorous activities and able to resume previous levels of daily and recreational activities . The three patients  with the AVN showed low scores prior to hemiarthroplasty whereas patient No 44 with the segmental collapse of the head was satisfied with the result as he had quite normal shoulder motion and only slight pain in vigorous activities. Patient No 45 with the nonunion had almost no motion in the shoulder before converted to RSA. All twenty-two patients who had been regularly employed prior to the injury in a sedentary job returned to their full work duties within 8 months. Of the fourteen patients who had been regularly employed in a manual job prior to the injury, 11 returned to their previous work duties.The average Constant-Murley score of the affected shoulder was 81,7 points  whereas the functional score as a percentage of the score in the unaffected shoulder was 86,2%. The average active elevation in a standing position was 1683.2o 45) was living in another area and missed our regular follow up visits. She had also two operations in the spine and she had received aggressive physiotherapy in her shoulder from the second postoperative week. Due to her spine problems she presented late (after one year) with a totally malfunctioned shoulder; she was unable to move her arm and the RC tendons had disappeared. A conversion to RSA resulted to a reasonable outcome with a constant score of 69 .No cases of severe malunion, tuberosities displacement, subacromial impingement and early osteoarthritis were noted. Solid union was achieved in all except one patient within three months . Absorption of the greater tuberosity was detected in five cases, three to four months postoperatively, without serious functional compromise of the shoulder. The degree of GTB displacement is a possible cause as in three of these cases it was displaced > 15 mm. Another possible cause is the intraoperative over-pulling of tuberosities by the surgeon as he tried to retract them below the level of the humeral head. Partial AVN of the head was seen in one patient in whom the integrity of the posteromedial hinge was disrupted 7 mm laterally. Computer tomography revealed necrosis of the lateral 1/3 of the head but the patient refused any further treatment. The only patient who developed nonunion (No 23) had an old injury (30 days old) and he referred to us by another hospital. He was initially treated conservatively with total immobilization of his shoulder. Because he was quite young, we decided to treat him by transosseous suturing despite the fact that a GTB osteotomy was considered necessary. This was an extended indication of our method and the outcome was presumable. One year later he underwent a glenohumeral joint release due to adhesive capsulitis and massive intra-articular ossifications and 3 years postoperatively a shoulder hemiarthroplasty was performed due to total collapse of the head and severe compromise of shoulder function . The second patient (No 43) didn’t conform to our rehabilitation protocol and the fracture was slightly displaced 3 weeks after the operation showing total AVN at 6 months postoperatively. Loosening of the knots might was a contributing factor to this early failure along with the fact that a fracture line through the anatomical neck was present intraoperative . A shoulder hemiarthroplasty was performed one month later resulting to an accepted outcome. The final AVN case was happened 12 months postoperative without any particular reason and it has been revised to shoulder hemiarthroplasty with a moderate outcome. Considering the pre-mentioned controversies the overall incidence of AVN and nonunion was 10.2% (5/49 cases) but only two cases could not be explained and can be attributed to the nature of the fracture.Special attention must be paid in our three cases with the total collapse of the head. The first patient  of the head to its anatomical position and internal fixation using tubular plates, locking plates, percutaneous pinning, screw-wiring techniques or transosseous sutures with the additional use of bone, synthetic or structural grafts in some reports , 25-30. et al. [et al. [et al. [et al. [et al [et al [et al [Jakob et al.  reported [et al.  reported [et al. , reporte [et al.  reported [et al.  followed [et al.  reported. [et al  reported. [et al  reportedl [et al  and Bognl [et al  reportedl [et al , 19 on 1l [et al , which wIn general, the use of heavy non-absorbable transosseous sutures is an attractive choice for fixation of 4-part valgus impacted fractures. After a midterm follow up of 43.8 months on average, we had four cases of AVN (8.1%) and one established nonunion (2%). The functional Constant score was 86.2% and almost all patients were satisfied with the result. The powerful characteristics of this study is the adequate patients sample, the long-term follow up and the well investigated clinical and radiological outcome but some limitations still exist: First, we attribute our good results to careful surgical technique, especially the solely use of osteosutures and minimal soft tissue dissection. Precise assessment of these surgical details is difficult. Second, the repeatability of radiographic measurements is lacking standardized methods to document as the humeral head is often either internally or externally oriented, depending on the radiograph plate and beam. An effort was made in all cases to obtain AP views in zero rotation and estimate the radiological parameters using special tools in our online PACS environment. Finally, some controversies exist about the consequences to normal shoulder anatomy by the minimally reduced humeral head. A biomechanical investigation may help in the future to combine the mechanical parameters with the long term clinical outcome.Despite these limitations, we recommend the use of open reduction and minimal internal fixation of 4-part valgus impacted fractures of the proximal part of the humerus in an attempt to achieve a satisfactory and stable reduction, adequate rotator cuff repair and immediate shoulder joint motion avoiding the complications of any hard material application.Advantages of this minimally invasive technique can be summarized to shorter operative time, no use of hardware, minimal soft tissue damage, low incidence of avascular necrosis, stable osteosynthesis with “tension band effect” and adequate rotator cuff repair allowing for early joint motion.


Morphological changes in apoptotic cells provide essential markers for defining and detection of apoptosis as a fundamental mechanism of cell death. Among these changes, the nuclear fragmentation and condensation have been regarded as the important markers but quantitative characterization of these changes is yet to be achieved. We have acquired confocal image stacks of 206 viable and apoptotic MCF-7 cells stained by three fluorescent dyes. Three-dimensional (3D) parameters were extracted to quantify and compare their differences in morphology. To analyze nuclear fragmentation, a new method has been developed to determine clustering of nuclear voxels in the reconstructed cells due to fluorescence intensity changes in nuclei of apoptotic cells. The results of these studies reveal that the 3D morphological changes in cytoplasm and nuclear membranes in apoptotic cells provide sensitive targets for label-free detection and staging of apoptosis. Furthermore, the clustering analysis and morphological data on nuclear fragmentation are highly useful for derivation of optical cell models and simulation of diffraction images to investigate light scattering by early apoptotic cells, which can lead to future development of label-free and rapid methods of apoptosis assay based on cell morphology. Apoptosis is an important mechanism of cell death and its research has wide implications in life science and clinical applications such as drug development for treatment of cancers and other diseases , 2. Apop2 at 37°C. Once MCF-7 cells reached approximately 90% confluence, they were detached with a solution of trypsin/EDTA followed by washing with growth medium. Stock solution of doxorubicin hydrochloride , prepared with deionized water, was added to cell media to induce apoptosis in MCF-7 cells by following established protocols [5 cells/ml and then seeded into 96-well plates with 100μl per well. After 24 hours incubation, 100μl of doxorubicin solution were added to obtain a final desired concentration (1~30μM) to treat cells by incubation at 37°C until the time of MTT assay or staining for confocal measurement.The human breast carcinoma cell line MCF-7 was purchased from the ATCC and maintained in DMEM medium supplemented with 10% FBS in an incubator with humidified atmosphere of 5% COrotocols –21. To irotocols . For thiControl and treated MCF-7 cells were stained with three fluorescent dyes of Syto-61 , Mito-Tracker Orange (M-7510) and Annexin V (V13241) for confocal imaging. The first two are cell-permeant dyes. The cyanine molecules of Syto-61 can have 40-fold or larger increase in its quantum yield for fluorescence emission once they bind to nucleic acids while affinity of Mito-Tracker Orange is affected by membrane potential of mitochondria. Annexin V, however, binds only to apoptotic cells with phosphatidylserine translocated from the inner to the outer leaflets of the cytoplasmic membrane and thus can be used to detect apoptosis.Stock solutions of Syto-61 and Mito-Tracker Orange were added to the cell suspension in a centrifuge tube at the concentration of 1μM and 0.2μM, respectively, after harvesting from a 96-well plate. The stained cells were incubated for 30 min before washing with medium by centrifugation. After aspiration of the supernatant, the remaining pellet were suspended in staining buffer, washed and re-suspended in the binding buffer of Annexin V. Annexin V was then added to the solution and the cells were incubate for 15 minutes at room temperature (~24°C) in the dark. Additional binding buffer was added at the end of incubation to the suspension which was placed on ice before imaging.For each imaging measurement with a confocal microscope , a suspension sample of triply stained cells with about 140 μl in volume was transferred to a depression glass slide and sealed by a cover glass. To speed up data acquisition with a 63x oil immersion objective, the cell density was kept relatively high so that each field of view (FOV) contained 5 or more cells that can be reconstructed from the same image stack. The fluorescence light signals from Annexin V, Mito-Tracker Orange and Syto-61 binding to their host molecules of specific organelles, upon excitation at 488, 555 and 639nm, respectively, were filtered and saved separately in the blue, green and red channels. Each color image slice consists of 512x512 pixels of 12-bit depth in each color channel. The suspension was translated along the z-axis by steps of 0.5 or 0.6μm in air to acquire a confocal image stack of the FOV. The averaged intensity of Annexin V fluorescence in the blue channel of the acquired image stack on cytoplasmic membrane voxels was used to determine if an imaged cell was viable or apoptotic after 3D reconstruction. A software named as CIMA  developed on Matlab  platform has been significantly improved to analyze MCF-7 cells stained with three fluorescent dyes for this study . We implOnce segmentation completes, the cytoplasmic membrane pixels determined in the red and green channels are compared for each slice and the one of bigger cell area is chosen for reconstruction. A refraction correction factor of 0.87 was determined for the true distance between consecutive image slices from z-axis step size in air . To makeCell survival curves were obtained using the MTT assay to confirm established protocols used in this study for ranges of doxorubicin dose D and treatment time t –21. The Confocal image stacks were acquired from viable and apoptotic MCF-7 cells in 8 suspension samples treated with doxorubicin and survival ratio S ranging from 30% to 70% as stated above and 1 control sample with doxorubicin replaced by growth medium. Reconstruction and analysis of 3D morphology have been conducted on 101 viable and 105 apoptotic cells with the improved CIMA software. The first notable results presented by these tables are the statistically significant increases of surface-to-volume ratios and surface irregularity indices for the nuclei and mitochondria of apoptotic cells. Combined with the considerable decrease in mitochondrial volume, these data agree well with the widely known occurrence of nuclear and mitochondrial condensation in apoptotic cells . It is asyto(r), is compiled in a histogram followed by a cubic smoothing over five-point window to reduce fluctuation in Isyto. A threshold Ith is set to the center intensity between Im and I5%, where Im is the intensity of maximum voxel number Nvoxel and I5% is the intensity when Nvoxle decreases to 5% of the maximum. If Nvoxel remains higher than 5% of its maximum before Isyto becomes saturated at 4095, Ith is set to the center intensity between Im and 4095. After determination of Ith, a nuclear voxel at r =  is labeled as either “valid” if Isyto(r) ≥ Ith or “null” otherwise. th for binary conversion of Syto-61 fluorescence in nuclear voxels and the insets show the results of binary conversion performed on slice #15 of both image stacks. The acquired confocal image stacks containing the two cells respectively can be seen in the two supplemental files of Nuclear fragmentation is a characteristic event of cell apoptosis  and quanr =  by examination of voxel density in a given volume. The conventional k-means algorithm, as implemented by the function of “kmeans” in Matlab, has been widely used to automatically determine the “closeness” among elements of a set in a parameter space and optimal arrangement of the elements in k clusters. The algorithm, however, requires a priori knowledge on k. For determination of an optimized k for a given nucleus, we developed a density based dividing scheme that is easy to implement and effective for our study in comparison to other schemes [r to the centroid are then calculated. A sphere centered at the centroid with radius equal to the distance of the furthest valid voxel from the centroid is used to obtain density ρ11, which is defined as the number ratio of valid nuclear voxels to all voxels enclosed by the sphere. The k is then incremented to 2 by dividing all valid voxels into two daughter clusters of 21 and 22 followed by minimizing their Euclidean distances to each centroid and calculation of ρ21 and ρ22 for the two clusters. The densities are then checked by the following inequalityTo quantify nuclear fragmentation, we set out to analyze the spatial distribution of valid nuclear voxels in 3D space of  schemes . It starThe cluster division is kept if the above is true or the average density of two daughter clusters becomes significantly larger than that of parent cluster. Otherwise the division is abandoned and all valid voxels remain in the parent cluster. The division process repeats until the inequality cl.The above clustering analysis relies on the existence of a peak value in the smoothed fluorescence histogram of nuclear voxels. Usually this should always be the case if the FOV of confocal imaging contains only one or two cells which allows adjustment of incident beam intensity and/or exposure time to avoid severe underexposure or overexposure on imaged cells. In this study we included larger number of cells in FOV to reduce data acquisition time and its effect on cells’ viability. The imaged cells and their nuclei have large variations in affinity to Syto-61 dye. As a result, it is very difficult to select appropriate imaging parameters so that all cells in FOV have peaked histograms for clustering nuclear voxels. Among the 101 viable cells with 3D reconstruction performed, 35 cells have Syto-61 fluorescence histograms that permit clustering calculations while 83 out of 105 apoptotic cells allow the same calculations. cl of nuclear voxels larger than 1 and both are at 2. In comparison, 9 out of 83 apoptotic cells have their Ncl ranging from 2 to 5 and cl = 5. The plots in Out of the 35 viable cells plotted in The 3D morphological parameters of apoptotic and viable MCF-7 cells have been obtained and analyzed through this study with a significantly improved image segmentation and 3D reconstruction software. Automated quantification of nuclear fragmentation has been achieved with a new method for clustering analysis of nuclear voxels in a 3D reconstructed cell according to their fluorescence distribution. Nearly all apoptotic cells as identified by the Annexin V stained cytoplasm membrane in confocal images were found to be in the early stage with statistically similar surface areas of cell, nuclei and mitochondria and volumes of the first two organelles. Despite the fact that they are in early stage, the apoptotic cells and their nuclei show significant increase in deviation of surface shapes from spherical ones or degree of irregularity. Loss of Syto-61 fluorescence in nuclei of these cells can also be observed in confocal image stacks and with the data of In summary, we have performed confocal imaging and 3D morphology analysis on 206 viable and apoptotic MCF-7 cells induced by doxorubicin and triply stained by Annexin V, Syto-61 and Mito-Tracker Orange fluorescent dyes. With a new method for clustering analysis of nuclear voxels, it has been shown that the apoptotic cells in early stage exhibit significantly increases in shape and molecular changes of cytoplasm, nucleus and mitochondria. These results deepen notably our understanding of early apoptosis in terms of 3D morphology and nuclear fragmentation, which allows future development of morphology-sensitive and label-free tools for apoptosis detection by, for example, diffraction imaging.S1 MovieThe cells were triply stained with Annexin V, Mito-Tracker Orange and Syto-61. This stack contains 5 apoptotic cells and 1 viable cell, which can be seen above the center line on the left side of the field-of-view and is absent of the fluorescence of Annexin V recorded in the blue channel of the color data file. The slice numbers are indicated at the lower-right corner.(MP4)Click here for additional data file.S2 MovieThe cells were triply stained with Annexin V, Mito-Tracker Orange and Syto-61. This stack shows one late-stage apoptotic cell above the center line to the right of the middle in the field-of-view that has fragmented nucleus and shrinking cytoplasm. The slice numbers are indicated at the lower-right corner.(MP4)Click here for additional data file.


Stress, depression, and anxiety among working populations can result in reduced work performance and increased absenteeism. Although there is evidence that these common mental health problems are preventable and treatable in the workplace, uptake of psychological treatments among the working population is low. One way to address this may be the delivery of occupational digital mental health interventions. While there is convincing evidence for delivering digital psychological interventions within a health and community context, there is no systematic review or meta-analysis of these interventions in an occupational setting.The aim of this study was to identify the effectiveness of occupational digital mental health interventions in enhancing employee psychological well-being and increasing work effectiveness and to identify intervention features associated with the highest rates of engagement and adherence.A systematic review of the literature was conducted using Cochrane guidelines. Papers published from January 2000 to May 2016 were searched in the PsychINFO, MEDLINE, PubMed, Science Direct, and the Cochrane databases, as well as the databases of the researchers and relevant websites. Unpublished data was sought using the Conference Proceedings Citation Index and the Clinical Trials and International Standard Randomized Controlled Trial Number (ISRCTN) research registers. A meta-analysis was conducted by applying a random-effects model to assess the pooled effect size for psychological well-being and the work effectiveness outcomes. A positive deviance approach was used to identify those intervention features associated with the highest rates of engagement and adherence.g=0.37, 95% CI 0.23-0.50) and work effectiveness  compared with the control condition. No statistically significant differences were found on either outcome between studies using cognitive behavioral therapy (CBT) approaches (as defined by the authors) compared with other psychological approaches, offering guidance compared with self-guidance, or recruiting from a targeted workplace population compared with a universal workplace population. In-depth analysis of the interventions identified by the positive deviance approach suggests that interventions that offer guidance are delivered over a shorter time frame (6 to 7 weeks), utilize secondary modalities for delivering the interventions and engaging users , and use elements of persuasive technology , which may achieve greater engagement and adherence.In total, 21 randomized controlled trials (RCTs) met the search criteria. Occupational digital mental health interventions had a statistically significant effect post intervention on both psychological well-being (This review provides evidence that occupational digital mental health interventions can improve workers’ psychological well-being and increase work effectiveness. It identifies intervention characteristics that may increase engagement. Recommendations are made for future research, practice, and intervention development. Nearly one in three workers in Europe  and the The workplace has been identified as a potentially ideal site for delivering mental health prevention programs  and incrSeveral meta-analyses and systematic reviews have found evidence for the effectiveness of digital psychological interventions delivered in nonworkplace settings for common mental health problems including depression, anxiety -23, and This systematic review and meta-analysis seeks to address this gap in the literature by identifying studies that deliver digital occupational mental health interventions and evaluating their effectiveness at increasing employee psychological well-being  and work effectiveness.Engagement and adherence are two of the major challenges to delivering and evaluating Web-based interventions -27. BoosThis review uses a positive deviance approach eg, ,33) to i to i33])The aims of this systematic review and meta-analysis are to evaluate the overall effectiveness of occupational digital mental health interventions for employee psychological well-being and work effectiveness and to identify, through the partial implementation of positive deviance methodology, which intervention features influence engagement and adherence. To this end, the review will address the following three questions:Are occupational digital mental health interventions associated with lower levels of stress and mental health symptoms post intervention than control groups?Are occupational digital mental health interventions associated with increased work effectiveness post intervention?Which intervention features are associated with the highest levels of engagement and adherence?This review was conducted following the Cochrane guidance for systematic reviews . We searTo meet the aims of this review, a study had to meet the following criteria: (1) use a randomized controlled design; (2) utilize a nontreatment, treatment as usual, or active control; (3) aimed at employed participants aged 18 years or over; (4) comprise a psychological intervention aimed at increasing psychological well-being  or work effectiveness ; (5) be delivered via the Internet, mobile technology, or a computer program; (6) written in English; and (7) offer sufficient post intervention data  in the paper or by contacting the authors to calculate the effect size for either a well-being or a work effectiveness outcome.Studies were excluded if they exclusively targeted people on extended sick leave or were targeting populations with complex mental health problems including post-traumatic stress disorder (PTSD), schizophrenia, or comorbid substance misuse. Studies were also excluded if technology was used purely as a medium for communication : the active element of the intervention had to be delivered on the Web or via mobile technology. Studies were also excluded if homework was completed on the Web but the intervention was delivered in person.The data was coded at four levels: study, intervention, participants, and outcomes. Further information about coding categories is available from the study registration .g) for both outcome variables  were produced using RevMan. The magnitude of effect size was interpreted using the classification given by Cohen  [The number of participants and the between group, post intervention means, and SD for the control and the experimental group on selected psychological measures  and selected work effectiveness measures  were entered into Review Manager (RevMan) version 5.3 and SPSS version 22 (IBM Corp). Where more than one measure was available, the measures were prioritized in the order given above. Forest plots of the between group, post intervention effect size (Hedges rge=0.8) .2) and the heterogeneity (I2) statistics. A large χ2 relative to its degree of freedom and a low P value provides evidence of heterogeneity [2 value of 25% suggests that heterogeneity is low, 50% suggests medium, and 75% suggests high [To test for the presence of heterogeneity of effect size, we used the chi-square  , an active control , or care as usual . Additionally, 17  of the studies completed an intention-to-treat analysis, and 4  completed a per-protocol analysis. Funnel plots for the effect sizes for the psychological wellbeing outcome and the work effectiveness outcome are shown in The 21 studies included in this review originated from 7 countries: 6 from the United States -46, 6 frThe sample size in the studies ranged from 48 to 762. Overall, the studies recruited and randomized 5260 participants: 2711 to a psychological intervention delivered predominantly on the Web and 2549 to a control condition. The data for 2438 participants was analyzed in the experimental group and 2360 in the control group. The discrepancy in numbers between randomized and analyzed is accounted for by study attrition ,56,58.Women made up 58% 3051/5260) of all randomized participants. All the studies were aimed at a working age population. The range of mean ages reported across the studies was 36.4 to 48.4 years in the intervention groups and 34.3 to 47.8 years in the control groups. Nine of the studies (43%) recruited from a targeted population, including individuals with elevated levels of depression ,54,56, s/5260 of Study attrition for the control and the intervention groups separately was available for 20 of the studies (one study reported combined study attrition ). The meIntervention completion (adherence) data was available for 19 of the studies . MosStudies were coded to see what if any elements of persuasive technology the interventions used to help support users to benefit from the intervention. They were coded using the classifications given by Fogg . These aPost intervention means, SDs, and group numbers were extracted from the 21 studies included in this review. Two separate meta-analyses were completed for (1) psychological well-being, and (2) work effectiveness. Of the 21 studies included in the psychological well-being meta-analysis, 13 were also included in the work effectiveness meta-analysis. Both analyses were conducted using a random-effects model.z20=5.24, P<.001) with a small effect size . The resulting effect sizes were significantly and highly heterogeneous .z12=3.00, P=.003) with a small effect size . The resulting effect sizes were significantly and highly heterogeneous .The results of both meta-analyses suggested that further subgroup analyses were warranted.21=6.9, P=.009). No significant difference was found between the two groups on the work effectiveness outcome.We conducted outlier analysis by examining the forest plots of standard mean difference effect sizes and CIs for both the psychological well-being measure and the work effectiveness measure. One study was identified as a possible outlier on the psychological well-being outcome  because Subgroup analyses for both the psychological well-being and work effectiveness outcomes were conducted looking at (1) therapeutic approach (CBT vs other), (2) guidance (guided vs nonguided), and (3) population . 21=3.63, P=.06), suggesting that for the psychological well-being outcome, the psychological approach used was not a source of heterogeneity. The pooled effect size for studies using the psychological approach of CBT was small , and for studies using other psychological approaches it was medium . Both are significant effect sizes .Subgroup analysis of the psychological well-being outcome comparing studies using CBT  with studies using other psychological approaches (k=9) showed that the groups were not significantly different from each other , suggesting that for the work effectiveness outcome, the therapeutic approach was not a source of heterogeneity. The small pooled effect size for studies using CBT  and other psychological approaches  are significant .Subgroup analysis of the work effectiveness outcome comparing studies using predominantly CBT (k=8) with studies using other psychological approaches (k=5) showed that the groups were not significantly different from each other , suggesting that for the psychological well-being outcome, guidance was not a source of heterogeneity. The pooled effect size for both groups was small  both were significant effect sizes .Subgroup analysis of the psychological well-being outcome comparing interventions providing guidance (k=10) with interventions that were self-guided (k=11) showed that the groups were not significantly different from each other . The pooled effect size for studies using interventions that are guided was a small significant effect size . The pooled effect size for interventions that are self-guided was a small nonsignificant effect size .Subgroup analysis of the work effectiveness outcome comparing interventions providing guidance (k=7) with interventions that were self-guided (k=6) showed that the groups were not significantly different from each other suggesting that for the work effectiveness measure, guidance was not a source of heterogeneity , suggesting that for the psychological well-being outcome, population was not a source of heterogeneity. The pooled effect size for the targeted working population was medium  and for the universal working population it was small . Both were significant effect sizes .Subgroup analysis of the psychological well-being outcome comparing a targeted working population (k=9) with a universal working population (k=12) showed that the groups were not significantly different from each other , suggesting that for the work effectiveness measure, population was not a source of heterogeneity. The pooled effect size for both groups was small ; both effect sizes were significant .Subgroup analysis of the work effectiveness outcome comparing a targeted working population (k=7) with a universal working population (k=6) showed that the groups were not significantly different from each other , and for the other studies it was 31% (SD 14.5). The mean of the highest intervention completion reported by the authors for the high engagement group was 68% (SD 22.0) and for the other studies it was 33% (SD 26.0).Interventions presented in the 7 studies in the high engagement group were reviewed. The interventions for 5 out of the 7 studies offered guidance (71%), compared with only 5/14 of the remaining studies (36%). The mean number of weeks that the intervention was delivered in the high engagement group was 6.6 , compared with a mean of 8.1  in the other studies. All 7 of the studies in the high engagement group described the use of persuasive technology , compared with 10/14 (71%) in the remaining studies .Six of the 7 studies (86%) in the high engagement group utilized a secondary modality for delivering the intervention and engaging users (4 studies used emailing and 3 studies used texting), compared with only 8 of the remaining 14 studies (57%). Only 2 of the 21 studies included in this review used a mobile phone app as their primary modality for delivering the intervention; both studies were included in the high engagement group.These findings suggest that interventions that achieve the greatest engagement and adherence offer guidance, are delivered over a shorter time frame (6 to 7 weeks), utilize secondary modalities for delivering the intervention and engaging users , and use persuasive technology . There is also a suggestion that a mobile phone app is a promising modality for engaging users of occupational digital mental health interventions.This review is the first meta-analysis that brings together RCTs of occupational digital mental health interventions and allows us to draw conclusions about both psychological well-being and work effectiveness outcomes. The adaptation of the positive deviance approach was helpful in enabling us to identify and explore in depth the features of high performing interventions in order to generate hypotheses about the intervention features that may promote engagement.The 21 studies included in this review recruited and randomized 5260 participants. They were predominantly recruited from the knowledge sector . The mean reported completion of interventions was 45%. These rates are similar to adherence rates reported for digital health (50%)  and digiOver half of the studies included in this review used interventions that were predominantly based on CBT (57%). The mean duration of the interventions was 7.6 weeks, with just under half (48%) of the interventions offering some form of guidance. The mean adherence to the interventions was 45%. In a review of digital health interventions, Kelders et al  reportedIn this review, 81% of the interventions described in the studies used some form of persuasive technology: tailoring was used by 57%, self-monitoring by 43%, and tunneling by 14%. Kelders et al  report tg=0.37, 95% CI 0.23-0.50, k=21), and a small positive effect on work effectiveness .Our results indicate that digital mental health interventions delivered in the workplace produced a small positive effect on psychological well-being (d=0.53 95% CI 0.36-0.69) [d=0.21, 95% CI 0.13-0.29) [g=0.28, 95% CI 0.12-0.44; anxiety g=0.29, 95% CI 0.06-0.53) [g=0.29, 95% CI 0.12-0.46) [Our findings situate occupational digital mental health interventions as comparable with other  occupational interventions in terms of impact on mental health and work effectiveness. The psychological well-being effect size is smaller but not significantly different from the medium effect size reported for a meta-analysis of occupational stress management interventions (36-0.69)  and is l13-0.29)  and heal06-0.53) , suggest12-0.46) , suggestThe psychological well-being effect size for occupational digital mental health interventions in our review is also comparable with digital mental health interventions delivered in health and community settings for adults with depression ,22 and sOur findings suggest that occupational digital mental health interventions are as effective at improving mental health outcomes as are other more traditional, nondigital occupational programs and other digital interventions delivered in nonoccupational settings. This is impressive given that the workplace context may impact on the way that digital mental health interventions are delivered and received. For example, it has been suggested that two of the advantages of digital health interventions compared with face-to-face or group interventions are increased accessibility, with participants being able to access at a time and a pace convenient for them ,27,30,69Furthermore, within an occupational setting, accessing digital mental health interventions may not be anonymous or even confidential. Access to the intervention may be managed through line management or occupational health; employees that do not have job autonomy may need to get permission to access the intervention during the working day, and employees working in an open plan office or sharing computer equipment may feel exposed when accessing the intervention at work. It is also possible that during the working day employees are so invested in appearing competent and strong that they are not willing or able to engage with a digital mental health intervention. The workplace may not be the appropriate setting to embrace the vulnerability that comes with acknowledging and addressing mental health challenges.Further research is needed to gain a clearer understanding of the challenges and benefits of delivering digital mental health interventions within occupational settings. Nevertheless, despite the possibility that the workplace may provide additional challenges to the way that these interventions are delivered and received, our study has shown that occupational digital mental health interventions are effective at improving psychological well-being and work effectiveness.The results of our review would suggest that as it is currently being delivered; CBT-based occupational digital mental health interventions are not producing superior results compared with digital interventions using other psychological approaches. Subgroup analysis comparing studies in our review using approaches described by the study authors as cognitive or cognitive behavioral therapy with studies using other psychological approaches revealed that the groups are not significantly different from each other on either the psychological well-being or work effectiveness measures. These findings are contrary to the established literature.A meta-analysis of digital psychological treatments for adult depression also found no difference between CBT and other approaches , but a mOne explanation for this may be that as they are currently being delivered, CBT-based digital mental health interventions are not optimized for delivery in occupational settings. In a recent review of occupational digital health, Lehr et al  observedNo significant difference was found in our review between interventions that provide guidance with those that are self-guided. This is different to the established literature, which has consistently found that guided Internet interventions are significantly superior to unguided interventions ,28,75-78It is worth noting that the positive deviance analysis found 71% of studies in the high engagement group offered guidance compared with only 36% in the remaining studies, suggesting that there may be a link between the provision of guidance and increased engagement with occupational digital mental health interventions.No significant differences were found in the review between studies that recruited a targeted population  and studies that targeted a universal population for either well-being or work effectiveness outcomes. However, there was a trend in both cases for studies with a targeted population to have a larger effect size, suggesting that individuals with raised levels of stress, depression, and insomnia benefit more from occupational digital mental health. One explanation for this might be that the measures used may not be sensitive to change at the lower end of the scale. Another explanation might be that participants with raised levels of psychological distress may be more motivated to implement the learning in the program and therefore produce more immediate post intervention results.These findings are contrary to a meta-analysis on workplace resilience interventions, which found weaker effects among targeted populations compared with universal populations at post intervention . That stMaximizing engagement with, and adherence to, digital heath interventions remains a pressing concern. The partial implementation of the positive deviance approach used in this review suggests that, within an occupational setting, These findings suggest that interventions that achieve the greatest engagement and adherence offer guidance, are delivered over a shorter time frame (6 to 7 weeks), utilize secondary modalities for delivering the intervention and engaging users , and use persuasive technology . These findings echo the literature on digital health interventions. In reviews of the design features that promote adherence to digital health interventions, evidence has also been found for increased guidance , the shoOnly 2 of the 21 studies included in this review used a mobile phone app as their primary modality of intervention delivery. Both studies were included in the high engagement group, suggesting that app technology is a promising modality for engaging users of occupational digital mental health interventions.This study highlights limitations in the broader digital mental well-being literature. One limitation is the small number of studies that measured occupational outcomes. Although the studies included in the review were aimed at employed participants and delivered within workplace contexts, most of them reported the reduction of psychological symptoms and failed to report occupational outcomes. We would recommend that future trials of psychological interventions delivered in the workplace incorporate occupational outcome measures, including work effectiveness.Another limitation was the considerable heterogeneity that was found across the studies. This included variation in the measures used (particularly in the work effectiveness measures), variations in the guidance given and the adherence, therapeutic approach and delivery of interventions, variation in the participants including country, type of organization, role and symptom severity, and variation in the quality of the study. The large number of unclear and high-risk of bias ratings limit the quality of the studies included in the review. The variation across the studies suggests that the results of our study should be interpreted with caution. We recommend that future research uses more robust study designs.The coding used in the review was limited by the description given about the interventions in the published literature. Many of the descriptions were short and appeared incomplete. This is a limitation described by other researchers ,62,80. NOther limitations specific to this review include the use in the positive deviance analysis of intervention completion and intervention group attrition as proxy measures of intervention engagement and adherence; the number of times that a participant logs in to an intervention or the number of modules that they complete cannot necessarily be taken as a measure of the extent to which they engage psychologically with the intervention ,81; LikeThis review has demonstrated that delivering digital mental health interventions in the workplace can result in improved psychological well-being and work effectiveness. Our findings suggest that interventions that achieve the greatest engagement and adherence offer guidance, are delivered over a shorter time frame (6 to 7 weeks), utilize secondary modalities for delivering the intervention and engaging users , and use persuasive technology . Further research is needed to test these hypotheses.We recommend that researchers and developers of occupational digital mental health interventions acknowledge the importance of the workplace setting in the content, delivery, and analysis of their interventions. We strongly recommend that therapeutic approaches incorporate relevant theoretical frameworks of occupational stress and that further research is conducted to better understand the challenges and benefits to delivering digital mental health interventions in the workplace. We also recommend that researchers incorporate in future research nonclinical measures of psychological distress and measures of occupational outcomes so that we can learn more about the psychological and occupational impact of digital mental health. A future area of research would be the long-term effect of these interventions.This review provides evidence that occupational digital mental health interventions can improve workers’ psychological well-being and increase work effectiveness and identifies intervention characteristics that may increase engagement. We recommend that researchers and intervention developers recognize that the workplace is a dynamic and complex environment that may affect the way that individuals receive and engage with digital mental health interventions.


Focal choroidal excavation is a choroidal pit that can be detected by optical coherence tomography. Central serous chorioretinopathy, choroidal neovascularization and polypoidal choroidal vasculopathy are pathologies associated with focal choroidal excavation. In this article, we present the follow-up and treatment outcomes of three eyes of two patients with focal choroidal excavation. Margolis et al.3 later used the term focal choroidal excavation for the areas of choroidal pitting observed near the macula on spectral domain (SD)-OCT in patients without posterior staphyloma or scleral ectasia. The condition causes symptoms like decreased vision and metamorphopsia, but its etiology is not fully understood. Studies have documented that focal choroidal excavation may be accompanied by choroidal vascular disorders including central serous chorioretinopathy (CSCR), choroidal neovascularization (CNV) and polypoidal choroidal vasculopathy (PCV), which are responsible for the visual symptoms.8Focal choroidal excavation is local idiopathic cupping of the choroid which is usually unilateral and not associated with any accompanying systemic disease.In this report we present the treatment and follow-up results of three eyes of two patients with the rare condition of focal choroidal excavation.2, 300 mW/cm2). The spot size was adjusted targeting the area of choroidal vascular hyperpermeability observed in the ICGA mid-phase from which the subretinal fluid originated.A 50-year-old female patient presented to the Ophthalmology Department of the İstanbul University İstanbul Faculty of Medicine with an approximately 2-year history of gradual vision loss in her left eye. Despite progressively decreasing vision in her left eye over the course of 2 years, she had not previously consulted any doctor about the problem. There was nothing extraordinary in the patient’s medical or family history. Her vision was 1.0  in the right eye and 0.05 in the left eye. Anterior segment examination was normal and intraocular pressure was 15 mmHg in the right eye and 16 mmHg in the left eye. Pigment epithelium changes were observed in both the right and left macula on fundoscopy . OCT exaAt 1 month after PDT, the subretinal fluid had resolved and visual acuity was 0.3. After 18 months of follow-up, no changes were observed in the lesions in the right eye, visual acuity in the left eye as maintained and there was no recurrence of subretinal fluid. OCT at the final examination showed continuity of the RPE and photoreceptor layer in the area of focal choroidal excavation, and no subretinal fluid was observed . On FFA,A 28-year-old female patient presented with metamorphopsia in her left eye starting 2 days earlier. There was nothing of note in her medical or family history, and her visual acuity was 1.0 in the right eye and 0.8 with -5.0 D refraction in the left eye. Anterior segment examination was normal. Fundus examination was normal in the right eye, but macular pigmentary alterations were observed in the left eye . On FFA 1 This excavation has been termed ‘nonconforming’ if photoreceptors are detached from the RPE, or ‘conforming’ when the RPE follows the contours of the photoreceptor layer.3 The nonconforming type exhibits a hyporeflective space on SD-OCT which does not appear in the conforming type.Focal choroidal excavation is a choroidal defect believed to be a congenital condition, though its etiology and pathogenesis are not yet fully understood, and is detectable on SD-OCT.1 Our patient with bilateral involvement also had extrafoveal excavation in the fellow eye, but visual acuity was not affected and no complications resulted.Focal choroidal excavation is generally a stable, unchanging lesion.8 It has not been determined whether CSCR leads to focal choroidal excavation or whether CSCR occurs as a complication of excavation. One of the proposed mechanisms is that excavation is mainly responsible for the pathology, causing atrophy of the overlying RPE and subsequent pump dysfunction, and CSCR occurs as a complication.7 It has also been proposed that CNV and PCV are both the result of choroidal ischemia in areas of anatomic anomalies.1CSCR, CNV and PCV are all pathologies which may accompany focal choroidal excavation.3 including 12 patients, CSCR was detected in 1 patient who later developed CNV during follow-up. Suzuki et al.7 evaluated 7 eyes of 6 patients with CSCR and focal choroidal excavation. Although the subretinal fluid resolved in all cases, 3 patients later progressed to nonconforming excavation, which exhibits the same hyporeflectivity on OCT as subretinal fluid. The authors attributed this to persistent subretinal fluid around the lesion. In their series of 41 eyes, Lee et al.1 detected CSCR in 10 eyes, CNV in 9 eyes and PCV in 1 eye; 2 eyes with CSCR were treated with low-fluence PDT. Despite resolution of the subretinal fluid in these patients, they continued to exhibit separation of the RPE and photoreceptor layer (nonconforming type). The nonconforming type was shown to be significantly associated with visual symptoms and CSCR.1 This was also true in our two patients, who exhibited nonconforming excavation and experienced visual symptoms. They both reverted to the conforming type, after PDT in the first case and after intravitreal bevacizumab injection in the second case. The resolution of the hyporeflective area evident on OCT in both patients may be related to the decreased choroidal permeability following PDT in the first patient and resolution of the active focal exudation in the retina after intravitreal bevacizumab injection in the second patient. The fact that patients transition between types supports the idea that hyporeflective areas on OCT in the nonconforming type may be due to subretinal fluid. Neither of our patients fully regained their vision after treatment, which may be attributable to the presence of chronic CSCR and subsequent RPE dysfunction.In a report from Margolis et al.In one eye of our first case, focal choroidal excavation remained static over the course of follow-up and did not require treatment. The same patient’s other eye was treated with low-fluence PDT and the affected eye of our second case was treated with intravitreal bevacizumab; both eyes showed regression to conforming excavation after treatment. Studies with larger patient numbers and longer follow-up times are needed to better understand the etiology, course and treatment options of focal choroidal excavation.Informed Consent: It was taken.Peer-review: Externally and internally peer-reviewed.