In this photodetector, the Nb2O5 layer detects the light, and the graphene improves the responsivity based on the photogating effect. The photocurrent and the percentage ratio of the photocurrent to dark current of the Nb2O5 photogating photodetector are compared with those of the corresponding photoconductive photodetector. Also, the Nb2O5 photoconductive and photogating photodetectors are compared with titanium dioxide (TiO2) photoconductive and photogating photodetectors in terms of responsivity at different applied (drain-source) voltages and gate voltages. The results show that the Nb2O5 photodetectors have better figures of merit (FOMs) in comparison with the TiO2 ones.In the present study, by adding graphene to a photoconductive photodetector with a niobium pentoxide (Nb The first synthetic single-layer graphene was made and characterized by Game and Novoselov in 2004. For this invention, Game and Novoselov received the Nobel Prize in Physics in 20102. In 2013, two-dimensional atomic sheets of graphene and a new classification of nanoscale materials that can be used in electronics were proposed3. The exciting properties of graphene include high charge mobility, excellent thermal conductivity, and high strength7. One of the applications of graphene is in photodetectors. Single-layer graphene can absorb only 2.3% of the irradiated light from 300 to 2500 nm, so it has low responsivity8. The responsivity of graphene photodetectors can be improved in different ways, including the use of microcavity structures9, quantum dots10, graphene nano disc arrays11, graphene waveguides13, heterostructures, and graphene incorporated with different materials15. High responsivity was reported in the graphene photodetectors with photogating effect18. In 2010, a graphene detector was made. The graphene detector had a responsivity of 6.1 mA/W at a wavelength of 1.55 μm19. In 2012, a graphene detector with a cavity was presented. The detector had a responsivity of 21 mA/W at a wavelength of 850 nm9. In 2015, a graphene and boron nitrate detector with an optical waveguide was presented; this detector had a responsivity of 0.36 A/W20. Various studies have been conducted on graphene and light absorption processes, including photovoltaic effect (generating photocurrent based on electron–hole separation under the electric field at the junction of the regions with different impurities), photogating effect , bolometric effect (change in conductivity as a result of light radiation and temperature increase), and thermoelectric effect (creating voltage according to the Seebeck effect due to the increase in the temperature of carriers)21. Since the responsivity of the photogating effect is much higher than that of other effects, the present study focuses on this effect. In photogating effect, one of the carriers is trapped in the absorber layer. In other words, the lifetime of the additional carriers increases as the carriers are separated from each other by defects and impurities. If one type of the generated carriers is trapped, it can generate an additional electric field such as a gate voltage to modulate the channel conductance26. Such detectors with small dimensions show high responsivity and limited response speed due to the prolongation of the lifetime of the additional carriers27. In 2012, a graphene structure with quantum dots was proposed. In this structure, a responsivity of 107 A/W was obtained at a wavelength of 532 nm10. In 2016, graphene∕SiO2/lightly-doped Si structure was used for high sensitivity and responsivity. The operating range was from the visible to near-infrared regions, and the responsivity was 1000 A/W at a wavelength of 514 nm. In this photodetector, due to the defects between SiO2 and the lightly-doped Si, electrons accumulate in the traps and create a negative gate voltage, causing more holes to be induced and thus increasing a high gain25. In 2018, black phosphorus (BP) with a direct bandgap of 0.3 eV was used as a light-absorbing material. At wavelengths of 655 nm, 785 nm, and 980 nm, the responsivities of 55.75 A/W, 1.82 A/W, and 0.66 A/W were obtained, respectively. Excited electrons are trapped in trap levels, and the holes pass through the graphene layer by the internal potential between graphene and BP. The lifetime of carriers increases with traps. Due to the high mobility of graphene, holes can flow in the circuit before recombining with electrons. The introduced structure works in the visible to near-infrared regions based on the photogating effect22. In 2018, Ti2O3 nanoparticles with a band gap of 0.09 eV were used to fabricate a detector in the mid-infrared spectrum. The mechanism is the same as before. This detector had a responsivity of 300 A/W for a wavelength of 10 μm28. In 2018, the photogating effect in graphene photodetectors was investigated using SiO2/n-doped Si substrate. At wavelengths of 450 nm and 1064 nm, the responsivities were 500 A/W and 4 A/W, respectively. The bending of the band at the Si/SiO2 interface separates the electron–hole pairs. Under the electric field, the electrons move towards Si while the holes are trapped at the Si/SiO2 interface; the accumulation of holes at the Si/Si2 interface acts like a positive gate and increases the Fermi level of graphene. This causes the graphene to become n-type24. In 2018, a graphene transistor was fabricated with an indium antimonide (InSb) substrate. A responsivity of 33.8 A/W with a photogating effect at a wavelength of 4.6 μm was achieved29. In recent years various photodetectors with TiO2 and Nb2O5 absorber layers in the UVA region have been presented30. In 2011, an Nb2O5 nanobelt was proposed, and at 1 V, a responsivity of 15.2 A/W was obtained31. In 2015, an Nb2O5 nanoplate photodetector was fabricated with a responsivity of 24.7 A/W at 1 V32. In 2021, a MAPbI3 nanowire photodetector was fabricated, and a responsivity of 20.56 A/W at 1 V was reported33. In 2023, a type-II heterojunction of TiO2 NTs/Cs3Cu2I5 nanoparticles hybrid fiber was presented with a responsivity of 26.9 mA/W at − 1 V34. The photogating effect can be investigated in three different structures, namely quantum dot10, bulk25, and thin film structures8. Quantum dots can be integrated into two-dimensional materials to achieve some advantages. As the first advantage, quantum dots with greater thickness resolve the issue of the low optical absorption of two-dimensional materials. The second advantage is that two-dimensional materials have high carrier mobility, and the third advantage is that some two-dimensional materials do not have a wide absorption spectrum while quantum dots compensate for this limited responsivity. For a two-dimensional material such as graphene, there is no mechanism to produce multiple carriers from one photon. By using quantum dots, a large number of holes can flow in the circuit, and as a result, the gain increases. This is because the lifetime of the trapped electrons is long, and the mobility of carriers in graphene is high. One of the disadvantages of quantum dots is their toxicity. Moreover, the dimensions of quantum dots change the bandwidth of the used materials. In bulk detectors, due to the defects between SiO2 and lightly-doped Si, electrons accumulate in the traps and create a negative gate voltage, causing the induction of more holes and thus increasing the gain. In other words, the bending of the band at the Si/SiO2 interface separates the electron–hole pairs. Under the internal field, the electrons move towards the Si substrate while the holes are trapped at the Si/SiO2 interface, and the accumulation of holes at the Si/SiO2 interface acts like a positive gate and increases the Fermi level of graphene. As a result, the graphene is converted into n-type graphene. A highly-doped silicon substrate is not used since it has additional carriers with a much shorter lifetime. The application of the bulk structure is limited to high-energy materials and X-rays25.Two-dimensional materials can interact strongly with light. One of these two-dimensional materials is graphene, which is a monolayer of carbon atoms tightly arranged in a crystal network with a two-dimensional honeycomb pattern2O5 (3.7 eV) and TiO2 (3.2 eV) absorber thin films are used based on the photogating mechanism. The use of broadband materials is an advantage for the photodetector because it operates at room temperature. By transferring graphene to the photoconductive detector, the responsivity increases approximately 20 times. The use of an Nb2O5 absorber layer is a new technique. The advantages of this technique are its low cost and simplicity of obtaining Nb2O5 without any special technology only by combining a few solutions. In the present study, a photoconductive detector with an Nb2O5 absorber layer and a graphene photogating photodetector with the same Nb2O5 absorber layer are compared in terms of responsivity and the percentage ratio of photocurrent to dark current. The responsivities of the photogating and photoconductive detectors with the Nb2O5 absorber layer are 12.69 A/W and 0.65 A/W respectively. The percentage ratios of photocurrent to dark current of the photogating and photoconductive detectors with an Nb2O5 absorber layer are respectively 2.84% and 0.16% at a drain-source voltage of 1.5 V and a gate voltage of 1 V. The responsivities of the TiO2-based photoconductive and photogating detectors, which are fabricated under the same laboratory conditions, are 0.45 A/W and 8.32 A/W, respectively. The percentage ratios of the photocurrent to dark current of the TiO2 photoconductive and photogating detectors are 0.16% and 2.84%, respectively. The responsivity of a photogating detector with an Nb2O5 absorber layer is about two times higher than that of a TiO2 photogating detector.In the present study, Nb2O5 absorber layer are shown in Fig. 2. As shown in Fig. 2 layer by electron-beam physical vapor deposition. Then, as shown in Fig. 2O5 absorber layer on SiO2. For the anodization of Nb, an electrolyte consisting of 1200 ml of ethylene glycol C2H6O2, 800 ml of H2O, and 160 g of (NH4) B5O6 was used. The Nb layer was connected to the positive pole and the platinum electrode, which was inside the anodization solution, was connected to the negative pole, and the anodization process was carried out. As shown in Fig. Total is the total width of the transistor, n is the number of distances, and w is the width of the transistor.The fabrication steps of the photoconductive and photogating photodetectors with an Nb36.To fabricate the photogating photodetector, all the steps are the same as performed for the photoconductive photodetector; only at the end, as shown in Fig. 2O5 heterostructures. By placing the graphene monolayer on the Nb2O5 layer, due to the difference in the Fermi level of the two materials, a built-in potential barrier is created between the two materials. Then, light radiation in the range of the band gap of the Nb2O5 layer leads to electron–hole pair production inside the Nb2O5 layer. Due to the potential barrier between the graphene and Nb2O5 layer, the electrons move towards the graphene layer, but the holes are trapped inside the Nb2O5 layer. The trapping of the holes changes the Fermi energy level of graphene and the resistance of the graphene channel, causing a large photocurrent26.Figure N-Methyl-2-pyrrolidone (NMP) solution at a temperature of 70 Graphene was transferred through a wet transfer method in seven stages, including etching the copper layer, substrate preparation, and graphene transferring. The process begins by eliminating the unwanted graphene that is placed under the copper layer during the CVD process. This process was done in a 20% nitric acid solution in which the substrate was kept for about five minutes. Then, the copper was etched using 0.2 M iron (III) chloride for almost two hours. After the metal residues were removed by RCA, the substrate was ready for graphene transferring, but before that, the substrate must be prepared. Next, the substrate was immersed in piranha solution at 70 2 layer and interdigit electrodes to the Nb2O5 layer. Figure –6 Torr to remove the PMMA residues. The average graphene sheet resistance was obtained by the van der Pauw method. An HP4450 semiconductor measurement device was used at a voltage of 1 V and a current of 1 μFigure 27. The gain can be obtained using Eq. , the extra electron reaches the anode, and another electron immediately enters the photoconductor to maintain the charge neutrality and drifts to the anode terminal. This process is repeated until the extra electron recombines with a hole. This process takes τlife on average, and the gain is greater than unity. However, if τlife < τtr, the extra electron recombines with a hole before the transit is completed. To achieve a gain of greater than unity without multiple electron–hole pair production, a higher power by an external circuit is needed. Equation  in the present study. The oxide-to-metal conversion factor of Nb is 2.7, meaning that for 1 nm of Nb, 2.7 nm Nb2O5 is formed.GS is the control voltage.To increase the current, materials with a high absorption coefficient are used because according to Eq. , with in to Eqs.  and 8),,ox decreSome of the figures of merit (FOMs) of the photodetectors are evaluated optically. The optical characteristics, except for some special cases, were obtained using a helium-cadmium laser at a power of 1 μW, a wavelength of 325 nm, and a chopper frequency of 3 kHz. As shown in Fig. 2O5 and TiO2 absorber layers were optically examined.Using this optical setup has two advantages. The first advantage is that the ambient noise is eliminated, and the second advantage is that even the lowest amount of photocurrent can be observed with this setup. The photoconductive and photogating photodetectors with Nb2O5 layer was obtained by anodizing with an oxide-to-metal conversion factor of 2.7. The Ti layer was deposited on the silicon substrate by sputtering, and TiO2 was obtained by the oxidation method with an oxide-to-metal conversion factor of 1.7.As shown in Table 2O5 photoconductive detector, and Fig. 2O5 photogating detector. As shown in Fig. DS) is applied to both ends of the graphene layer, and the control voltage (VGS) is applied to the silicon substrate through ohmic contacts.Figure 2O5 absorber layer. The photocurrent of the photoconductive photodetector increases from 0.533 to 0.64 μA. By adding graphene, the photocurrent increases from 7.87 and 12.69 μA in the drain-source voltage range of 0.1–1.5 V. As the value of VDS increases, due to the reduction in the potential barrier, electrons more easily travel from Nb2O5 to graphene, and as a result, the increase in Iph is greater. In other words, according to Eq. , the carrier trapping time increases, and thus, the responsivity and photocurrent increase. The responsivity is also dependent on the initial energy level of the graphene layer. At a drain-source voltage of 1.5 V, the ratio of responsivity of the Nb2O5/Gr photodetector to that of the TiO2/Gr photodetector is about 2, and the ratio of the responsivity of the Nb2O5 photodetector to that of the TiO2 photodetector is about 1.5. This indicates the better performance of the Nb2O5 absorber layer compared to the TiO2 absorber layer while both of these layers were made under the same laboratory conditions.Figure 2O5 absorber layer are higher than those with the TiO2 absorber layer. The value of As shown in Table GS. However, in the photogating detectors, the carrier trapping time increases due to the photogating effect, so responsivity and photocurrent increase. The responsivity is also dependent on the initial energy level of the graphene layer. Therefore, it is proven that the increase in the responsivity of the photodetector with increasing VGS is because of transferring the graphene layer to the TiO2 absorber layer.Figure 2O5 and TiO2 photogating detectors are located at 20 V and 15 V, respectively. At the Dirac points, not only the photogating detectors have the highest responsivity, but also the curves have the highest slope around the Dirac points. As shown in the curves of the photogating detectors, further increase in the gate voltage has a downward trend, and responsivity decreases. The reason for this is shown in Fig. d/∂Vg, and the maximum of the responsivity curve, which is shown in red, is located at the points with the highest slope.As shown in Fig. 2O5 absorber layer was calculated as an FOM. With the increase in frequency, the frequency response criterion does not decrease substantially. These results indicate that both photodetectors can be used in applications, such as UV imaging and many modern systems, with a frequency requirement of up to 5 kHz.As shown in Fig. 2O5/TiO2 absorber layers (presented in this study) and previous detectors presented in other articles with the same absorber layer materials. According to this table, detectors with the Nb2O5 absorber layer have better responsivity than those with the TiO2 absorber layer. The Nb2O5 Nanobelts and the Nb2O5 nanoplates detectors have a better responsivity than the thin-film Nb2O5 photoconductive and photogating detectors. The Nb2O5 nanoplates detector has a better responsivity than the Nb2O5 Nanobelt, but the fabrication of the thin-film Nb2O5 detector is simpler than Nb2O5 nanoplates and nanobelts detectors.Table 2O5 absorber layer was used for fabricating a graphene detector based on the photogating effect. Moreover, an anodizing process was employed to produce this absorber layer from a thin layer of Nb. These processes have not been conducted in the literature and were presented in this study for the first time. It is worth noting that compared to photodetectors with a TiO2 absorber layer, the photodetectors with an Nb2O5 absorber layer performed better in terms of the cost, simplicity of the fabrication process, and high value of responsivity. With 325-nm laser radiation, 1 μW power, at a drain-source voltage of 1.5 V, and a gate voltage of 1 V, the responsivities of the photoconductive and photogating detectors with the TiO2 absorber layer were 0.45 A/W and 8.32 A/W, respectively, while the responsivities of the photoconductive and photogating detectors with the Nb2O5 absorber layer were 0.65 A/W and 12.69 A/W, respectively. Moreover, the percentage ratios of the photocurrent to dark current of the photoconductive and photogating detectors with the TiO2 absorber layer were 0.003% and 0.111%, respectively. However, the percentage ratios of the photocurrent to dark current of the photoconductive and photogating detectors with the TiO2 absorber layer were 0.16% and 2.84%, respectively. Therefore, the responsivities and the percentage ratios of the photocurrent to dark current in detectors with the Nb2O5 absorber layer were better than the detectors with the TiO2 absorber layer.An Nb


Sarcoidosis is a multisystem granulomatous disease of unknown origin. The most frequent localizations are thoracic lymph nodes and/or parenchymal lung disease, nevertheless any other organ may be involved. Musculoskeletal sarcoidosis, previously considered a rare manifestation of the disease, is presently recognized with increasing frequency, due to the development of modern imaging modalities. The classical X-ray sign of bone sarcoidosis is the image of lace in the phalanges of the hands. Most other locations present with atypical radiological images. Therefore, they may mimic metastatic neoplastic disease, especially when they are the first sign of sarcoidosis not previously recognized. On such occasions, none of the imaging methods will give the correct diagnosis, histopathological verification, monitoring of lesions or clinical data in a patient with confirmed sarcoidosis are indicated. The article summarizes the current status of knowledge concerning the recognition and therapy of bone sarcoidosis. In addition, an illustrative case of patient with bone and bone marrow sarcoidosis is presented.  Sarcoidosis is a rare systemic granulomatous disease of unknown etiology. It may affect multiple organs; most frequent manifestation concerns thoracic lymph nodes and/or parenchymal pulmonary disease . AccordiPulmonary and nodular sarcoidosis rarely causes severe symptoms, usually being a self-limited, self-curable disease in stage 1, with an increasing percentage of those who need treatment in stages 2 and 3 and causing lung fibrosis in a small proportion of patients .Extra-pulmonary sarcoidosis is diagnosed in 50–74% of patients. Most life-threatening symptoms are related to cardiac sarcoidosis, and sarcoidosis-related hypercalcemia, which is usually combined with acute renal failure . AnotherMusculoskeletal manifestation includes bone, muscle and joint involvement; it may present as bone lesions, arthralgia, and pathological fractures . AccordiBone sarcoidosis may occur at any location: hands and feet, followed by the long bones of the arms and legs, pelvis, spine, and ribs. The bone involvement may be focal or diffuse and can affect one or multiple sites. Although hands and feet are considered the most common localization of bone lesions in sarcoidosis, the involvement of the axial skeleton is increasingly noted. Sparks et al. described the most frequent location of bone lesions in the spine and pelvis . Zhou etImaging plays a crucial role in the diagnosis and management of bone sarcoidosis. Progress in imaging technology improved our understanding of the disease and facilitated diagnostic tissue sampling. Bone sarcoidosis usually is differentiated from bone metastatic disease, but other rare diseases, such as Blau syndrome (autoinflammatory syndrome related to the NOD2 genetic heterogeneity), should also be taken into consideration . We presDiagnostic imaging modalities commonly used for musculoskeletal sarcoidosis include X-ray, ultrasonography, computed tomography, MR imaging, and FDG-PET/CT as well as other radioisotope methods. Imaging when musculoskeletal involvement is suspected in a patient with sarcoidosis allows the lesions to be localized and their extent and severity to be determined.X-rays, ultrasound, computed tomography, and magnetic resonance imaging are used to assess local extension. Whole-body MR examination, PET-CT, and scintigraphy are modalities that show the extent of lesions throughout the musculoskeletal system.Identifying bone and joint lesions in a sarcoidosis patient and implementing appropriate treatment is important because of possible complications such as pathological fractures of the bones and vertebral bodies. Imaging methods are used for follow-up during treatment.Modalities that do not use ionizing radiation, such as magnetic resonance imaging (MRI), are particularly recommended for this purpose.X-ray remains the first-line imaging modality for the detection of bone involvement in sarcoidosis. However, it is not sensitive enough to detect early bone involvement. Therefore, the use of more sensitive imaging modalities, such as CT and MR imaging, may be necessary.Bone sarcoidosis was first described in 1903 by Kreibich as the image of lace in the phalanges of the hands and this is considered the classic presentation of small bone involvement . The typical cystic X-ray pattern of bone sarcoidosis was described for small bones of the hands only . Other sIn the case of typical bony lesions of the phalanges of the hands, extending the diagnosis to MR imaging is not necessary.CT is a sensitive imaging modality that can detect smaller bone lesions in sarcoidosis. It can provide detailed information on the extent and location of the bone involvement. CT is superior to X-ray in detecting bone lesions and could provide valuable information for treatment planning. The CT images categorize the bone lesions as osteolytic, osteosclerotic or mixed lytic-sclerotic . EvaluatComputed tomography, although showing greater sensitivity compared to X-ray, is a less sensitive method compared to MRI, besides being associated with ionizing radiation doses.The CT-guided biopsy of the lesions enables collection of a sample for histopathological examination. The presence of non-caseating granulomas in the collected material is often the only method of confirming the diagnosis and differentiating bone sarcoidosis from other conditions, such as metastases or multiple myeloma. Ultrasound examination is a useful method for evaluating joint cavity effusion in cases of acute and chronic arthritis in the course of sarcoidosis, also allowing assessment of synovium, tendons and cartilage. Under ultrasound’s guidance joint fluid can be collected for examination. This modality is also useful in visualizing sarcoid changes in soft tissues and can be used to localize and biopsy the lesions.MR is a highly sensitive imaging modality that can detect bone marrow involvement in sarcoidosis. It also provides the detailed information on soft tissue involvement, synovitis and joint inflammation. Occasionally, MR images detect clinically and radiologically silent lesions a,b.Moore et al. in a study of 42 patients with sarcoidosis showed that MR imaging detected more lesions in the long bones and axial skeleton compared to X-rays . The senA routine MR examination protocol for the musculoskeletal system including T1-weighted, T2-weighted and STIR images should be supplemented with the administration of gadolinium contrast agent and diffusion-weighted images.It is important to note that MR imaging does not expose the patient to ionizing radiation, so it can be used to monitor lesions under treatment.PET/CT is a combined imaging modality that obtains the metabolic information from a PET scan and the anatomical information from a CT scan. It can be useful in detecting bone involvement in sarcoidosis, particularly in cases where other imaging modalities are inconclusive. FDG-PET/CT study allows detection of metabolically active foci in the musculoskeletal system and assessment of the extent of the disease. Although the sensitivity of PET-CT in bone sarcoidosis is sometimes reported to be 98.1% , specifiDue to its high sensitivity, the examination is useful for the evaluation of asymptomatic lesions and may be useful for sarcoidosis patients with unspecified bone complaints .A decrease in the FDG uptake in the follow-up PET/CT study is indicative of a metabolic response associated with regression of the sarcoid foci. A promising diagnostic tool for musculoskeletal sarcoidosis appears to be a hybrid of PET and MRI  Figure a,b.Gallium scintigraphy has been used for many years in the diagnosis of sarcoidosis, including those involving the musculoskeletal system. The diagnostic efficacy is enhanced by the use of single proton emission CT (SPECT) and SPECT-CT. Sarcoid lesions show increased uptake of the 67 Ga tracer. Various studies have determined the sensitivity of gallium scintigraphy in the evaluation of active lesions in sarcoidosis to be between 60 and 90% with a specificity of approximately 50% ,17,18. IWhen comparing FDG-PET/CT and gallium scintigraphy, it should be noted that the radiation dose in scintigraphy is three times higher and the acquisition takes place 24 h after the uptake of the radiotracer.Sarcoidosis-associated arthritis may be acute or chronic. Acute arthritis, diagnosed more frequently than chronic, is a self-limiting disease often diagnosed as a component of Löefgren’s syndrome . In 40% Chronic arthritis, either mono-articular or poly-articular, occurs in the later phases of the disease, usually as a part of a multisystem manifestation. In addition to synovitis a,b, erosLong-lasting joint inflammation leads to the narrowing of the joint space. In the sarcoid arthritis diagnostic imaging, we mainly use X-ray, US, and MR imaging. MRI shows with high sensitivity the joint effusion and features of synovitis, cartilage destruction, and inflammatory changes of periarticular structures such as peritendinitis, tendinitis or bursitis a,b 20]..20].Only the radiological pattern of the lesions in the phalanges of the hands and feet, resembling a lace on X-ray, is described as characteristic of bone sarcoidosis.The radiographic appearance of phalanges occupied by sarcoidosis includes lytic lesions of various sizes, called cysts. Cystic lesions, mostly punched-out, may be accompanied by soft tissue nodules. The presence of large cysts increase the risk of pathological bone fracture  Figure a,b. NumeFeatures of bony destruction may be permeative and cause scalloping of the cortex, whereby cortical margins are preserved. Bone destruction with moth-eaten pattern may involve the cortex, usually with associated soft tissue swelling . The corIf the hand or feet bone lesions are isolated, they require differentiation from enchondroma, subchondral cysts, metastases, fibrous dysplasia or osteomyelitis.In the long bones and axial skeleton, bone lesions can have an osteolytic, osteosclerotic or mixed appearance. Osteosclerotic lesions are more common in the spine . Unlike MR imaging is a highly sensitive method for the diagnosis of bone sarcoidosis, but the lesions are not specific. Moreover, the serum hypercalcemia that may be present both in sarcoidosis and in metastatic bone disease is not helpful in differential diagnosis. Bone marrow sarcoid foci are hypointense on T1-weighted images and hyperintense on T2-weighted and STIR image, with the same appearance as metastases, multiple myeloma or lymphoma  Figure a,b. In TThe outlines of the lesions can be smooth or irregular, and sometimes the presence of normal fatty bone marrow within the lesion can be seen, which was thought to be an indicator of the benign nature of the lesion  Figure . The preHowever, differentiation between sarcoidosis and metastases may be difficult on a routine MR examination protocol. Moore et al. showed in an analysis of MR images of 34 patients with metastases and spinal sarcoidosis that it is not possible to differentiate between lesions based on routine MR images alone .2/s [The specificity of MR imaging may be improved by diffusion-weighted imaging . Conte e2/s . This stMuscle involvement in sarcoidosis may be asymptomatic or may present as acute or chronic myositis and sometimes it presents as painful nodules. Symptoms of muscle sarcoidosis are seen in only 1% of patients, with chronic myopathy being the most common form of the disease . GalliumThe optimal therapy for bone sarcoidosis is not known and there is no consensus concerning the treatment of osseous involvement in the disease. Neither ATS nor the European Respiratory Society (ERS) nor the British Thoracic Society (BTS) sarcoidosis guidelines specify the best treatment for bone localizations ,22,23. ASarcoidosis frequently undergoes spontaneous regression without causing any permanent damage to the affected organs . SpontanAsymptomatic patients probably do not require treatment, although the indications for therapeutic interventions are not well defined. Treatment in sarcoidosis with osseous involvement is usually indicated in case of uncontrolled pain, stiffness, or bone destruction. It is not known whether early therapy can affect the course of the disease.Non-steroidal anti-inflammatory drugs (NSAIDs) can be effective for symptoms relief. Glucocorticoid (GCS) oral therapy is the most frequently used first line treatment, mostly prednisone 20–40 mg, gradually reduced to 10 mg daily—the dosage is adjusted according to the clinical response. GCSs can decrease pain, but they do not normalize the bone abnormalities. Moreover, prolonged use of corticosteroids may increase the risk of osteoporosis. A careful follow-up with bone mineral densitometry and determination of calcium metabolism must be performed during steroid therapy ,28. For refractory cases of bone sarcoidosis, steroid-sparing agents may need to be added. Methotrexate (MTX) 15 mg weekly, azathioprine (AZA) 50–100 mg twice daily, and tumor necrosis factor (TNF) alpha inhibitors are the most common. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are used as the third line of therapy . MTX useIndications for operative interventions in osseous sarcoidosis include irreversible bone pain, neurological involvement, and radiographic evidence of severe cortical destruction such as spinal instability . For patIn an American study of 24 patients with bone sarcoidosis, who had the median follow-up of 5 years, investigators found favorable clinical course in most cases . After iA 34-year-old man was admitted to the pulmonary department due to non-productive cough, pain and swelling of the knee and ankle joints, and increased body temperature to 39 °C for 10 days a few weeks before admission. Ambulatory chest computed tomography (CT) revealed bilateral hilar lymphadenopathy. 9/L , neutrophils count—3.21 × 109/L , C-reactive protein (CRP)—11.4 mg/L , erythrocyte sedimentation rate (ESR)—21 , and angiotensin-converting enzyme level (ACE)—77.3 IU/L . During the six-minute walking test (6 MWT) the patient covered 576 m, without desaturation. Body plethysmography showed a mild degree of bronchial obstruction and a mild decrease in lung diffusion capacity for carbon monoxide (TLCO)  was 115/90 mmHg, heart ratio (HR)—97/min, saturation O2—98%. The physical examination was normal, joint swellings subsided. Laboratory test revealed white blood cell count (WBC)—5 × 10e (TLCO) . Bronchoscopy with bronchial biopsy and an endoscopic ultrasound–guided lymph node biopsy (EBUS-TBNA) were performed. Pathologic examination of bronchial mucosa and lymph node biopsies were inconclusive. Broncho-alveolar lavage fluid (BALF) revealed increased lymphocytes count (43% of cell population), with a high CD4/CD8 index (9.96). Ziehl–Neelsen smears and cultures of bronchial washings for tuberculosis and other pathogenic organisms were negative. Finally, stage I sarcoidosis without pathologic confirmation was diagnosed. The patient did not receive any treatment. Subsequent chest CT showed partial regression of nodal lesions and the presence of small parenchymal nodules in the lungs. During the further follow-up, the patient reported pain in the lumbar spine and paresthesia of lower limbs. X-ray examinations of the spine did not show any evident changes. Laboratory examinations revealed normal serum calcium level and increased calcium level in a 24-h urine test . Abdominal CT showed spleen enlargement with focal lesions suggestive of sarcoid granulomas, calcifications in the left kidney, as well as enlarged abdominal lymph nodes. Chest CT revealed progression of nodal and parenchymal lesions. An MRI scan of the lumbar spine and pelvis was performed. The lumbar spine MRI revealed protrusion of an intervertebral disc with compression on the dural sac and nerve roots, which presumably caused the symptoms. Moreover, the images of lumbar vertebrae and pelvis showed disseminated, small enhancing lesions a,b, whicIt was decided to repeat bronchoscopy. Pathological confirmation of sarcoidosis was obtained from a biopsy of the bronchial mucosa (non-necrotizing granulomas and multinucleated giant cells). To exclude other than sarcoidosis changes in the bones and bone marrow, the patient was consulted in hematology and orthopedic medical centers. Iliac bone biopsy revealed multinucleated giant cells and epithelioid granulomas without necrosis. In bone fragment-containing bone marrow, the image was suggestive of sarcoid granulomas as well. Due to confirmation of sarcoidosis with bone and bone marrow involvement and progression of lung disease, prednisone at a dose of 30 mg per day and methotrexate at a dose of 20 mg per week was implemented. As a result of treatment, almost complete regression of lung disease in the control chest CT, and normalization of respiratory parameters, was observed. Normalization of calcium level in 24-h urine test , and regMusculoskeletal involvement in the course of sarcoidosis is increasingly recognized due to implementation of modern imaging techniques. The most troublesome situations concern the patients with focal bone disease, recognized in patients without the signs of pulmonary sarcoidosis. Tissue biopsy is often required to differentiate between bone sarcoidosis and metastatic neoplastic disease because MR images of bone lesions are nonspecific, mandating differentiation between sarcoidosis foci and metastatic lesions or multiple myeloma. Modern imaging techniques facilitate tissue sampling and enable monitoring of the disease course. Although the spontaneous regression of bone sarcoidosis is possible, some patients require immunosuppressive therapy to achieve the remission of the disease.


The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol–iron complex, which were discovered over 40 years ago, highlight the difficulties, complexities and efforts in general orphan drug development programs originating from academic centers. Deferiprone is widely used for the removal of excess iron in the treatment of iron overload diseases, but also in many other diseases associated with iron toxicity, as well as the modulation of iron metabolism pathways. The maltol–iron complex is a recently approved drug used for increasing iron intake in the treatment of iron deficiency anemia, a condition affecting one-third to one-quarter of the world’s population. Detailed insights into different aspects of drug development associated with L1 and the maltol–iron complex are revealed, including theoretical concepts of invention; drug discovery; new chemical synthesis; in vitro, in vivo and clinical screening; toxicology; pharmacology; and the optimization of dose protocols. The prospects of the application of these two drugs in many other diseases are discussed under the light of competing drugs from other academic and commercial centers and also different regulatory authorities. The underlying scientific and other strategies, as well as the many limitations in the present global scene of pharmaceuticals, are also highlighted, with an emphasis on the priorities for orphan drug and emergency medicine development, including the roles of the academic scientific community, pharmaceutical companies and patient organizations. Iron is one of the essential metal ions found in all cells of the body, as well as in cancer cells and microbes. It is generally required for many enzymes and other proteins performing vital bodily functions and is involved in many physiological and biological processes, such as oxygen transport, storage and utilization; energy transduction; growth and development; lipid metabolism; and DNA synthesis ,2,3.Iron is tightly controlled in the human body using different mechanisms, pathways and proteins, which are involved in its uptake, distribution, utilization, recycling and excretion. Each cell requires and utilizes different amounts of iron and also other essential metal ions such as zinc and copper for different biological functions ,4,5,6,7.There is wide variation in the requirements for iron and other metals for different cell types, which in the case of iron is mainly reflected by the number of transferrin receptors on the cell membrane ,10,11,17It is estimated that about 4.5–5.0 g of iron is present in a 70–75 kg normal adult man, which is distributed in the blood and different organs. Most of the iron is in the form of heme in the proteins hemoglobin (2.3–2.6 g) in red blood cells (RBC) and myoglobin (0.32–0.40 g) in muscle. Iron is also distributed in the body, mainly in the form of polynuclear ferric oxyhydroxide phosphate complexes in the iron storage proteins ferritin (0.7 g) and hemosiderin (0.3 g), which are mainly found in the liver, spleen, muscles and bone marrow. Smaller amounts of iron are also found in mitochondrial cytochromes (17 mg), catalase (5 mg), transferrin (4 mg) and non-heme iron-containing enzymes (0.1 g) .2+) or ferric (Fe3+) state forms, and is always bound to different ligands containing oxygen, nitrogen and sulfur [−18 mol/L), since it mostly precipitates by forming insoluble polymeric ferric oxyhydroxide complexes with high stability constants (log K = 38) [At normal physiological conditions and pH levels, iron is mainly found in the ferrous (Fed sulfur . Under t K = 38) . In geneIron imbalance is associated with serious clinical conditions affecting many categories of patients ,3,20,21.There are many other diseases related to iron metabolism imbalances in addition to IDA, including the hemoglobinopathies and idiopathic hemochromatosis, which are the most common genetic diseases affecting humans ,47,48,49The major form of treatment of thalassemia major is regular red blood cell transfusions every 1–4 weeks and daily chelation therapy ,51. MultThere are many other diseases related to iron and other metal imbalance and toxicity conditions, where iron-chelating drugs and iron chelator complexes could be used as originally suggested in 2003 . Many ofDeferiprone and the tri-maltol–iron complex, also known as ferric maltol, Feraccru or Accrufer, were originally designed, synthesized and screened in vitro and in vivo in 1981 following the initiation of an academic project in 1978 ,61,62,63The path of development and the journey through the years of each of these drugs were completely different, with many difficulties and many intriguing turns of events related to research findings and the involvement of different academic centers, pharmaceutical companies, physicians, research investigators and patient organizations, which continue today ,63.The design and development of L1 and the maltol–iron complex were initiated in the biological chemistry department of the University of Essex, United Kingdom (UK), while working on a hemoglobin project in 1979 ,64. The Based on these prototype structures of alpha-ketohydroxypyrone and alpha-ketohydroxypyridine classes of chelators, about half a dozen new compounds were initially synthesized, including L1, and about a dozen commercially available compounds including maltol were screened in vitro in different models for their iron-binding and other properties . The in Due to lack of different screening facilities at Essex University for investigations related to the chelating compounds, including those for cell and in vivo studies, the developmental program for the iron chelators was partly moved to University College London Medical School (UCLMS) through contacts with the UKTS and associated researchers in UCLMS. In this context, new experimental screening programs were developed and showed that L1 was the most effective chelator for iron mobilization from transferrin and ferritin and also from iron-loaded mice following oral and intraperitoneal administration routes . SimilarThe situation was particularly urgent and frustrating regarding the development of orally administered L1 in thalassemia, since many patients’ lives were at risk because of complications with the 8–10 h long subcutaneous (sc) administration of DF, including compliance, toxicity and efficacy concerns . In the The pressure by thalassemia patients and parents was mounting for the rapid development of oral chelation therapy by the early 1980s. As a result, in 1985, the UKTS sponsored the continuation of the iron chelation project at the Royal Free Hospital School of Medicine (RFHSM) of the University of London from where the first publications of the iron removal effects of L1 in comparison to parenteral DF in mice and rabbits and later in other animal species were reported ,71,72,73The higher levels of safety and efficacy of L1 in different animal species in comparison to many other alpha-ketohydroxypyridines studied at the RFHSM, and several other developments such as the simple inexpensive synthesis of L1 and other alpha-ketohydroxypyridines, prompted the initiation of an application to the UK governmental regulatory authorities for clinical testing ,79. The In the meantime, several kilograms of L1 were prepared using the new method of synthesis, which was encapsulated in 0.5 g quantities by the pharmacy of Royal Free Hospital using gelatin capsules . The encIn the meantime, fierce competition against the development of L1 was initiated by academic and commercial groups, which began from the time of discovery and continues today for different reasons ,63. For Following the initial clinical trials at the RFHSM with L1, many other academic hospitals caring for thalassemia and other categories of transfusional iron-loaded patients worldwide expressed a great interest in joining the clinical trials and testing L1 in their institutions using the same protocol. In most cases, the vast majority of patients selected for the clinical studies were not responding or were intolerant to sc DF therapy. In many of the external clinical studies, L1 was supplied from the RFHSM  to instiWhile the clinical trials with L1 were continuing and expanding worldwide, an incidence of agranulocytosis was reported in 1989 in a Blackfan–Diamond patient at the RFHSM, causing the postponement of the L1 trials at the RFHSM to the dismay of the UKTS’ investigating team . SeveralDespite the encouraging pre-clinical and clinical results with L1, there was insufficient interest from major pharmaceutical companies for its commercial development, mainly because of financial considerations and especially the small number of thalassemia patients that require treatment in developed countries. In the meantime, many steps were taken to further advance the development of L1, including an application by the inventor proposing an international non-proprietary (INN) name for L1 in 1991, which resulted in the adoption by the World Health Organization (WHO) of the INN name deferiprone .Unexpectedly, the major breakthrough in the pharmaceutical development of L1 came from India, which played a leading role in the pharmaceutical development and distribution of the drug in developing countries. This development came about following a collaborative project that was initiated between a parent of a thalassemia patient and member of the Thalassemia Society in Mumbay, India, and the UKTS-sponsored group at the RFHSM. The parent also worked at the Indian generic pharmaceutical company Cipla, which was one of the leading generic drug manufacturers in India ,95,98. IAt about the same time as a BBC TV program highlighting the developments in India, the administration of the RFHSM decided to terminate all research on thalassemia supported by the UKTS, including the research on L1 and chelation therapy in general. This was a major drawback in the ongoing projects of L1, which continued elsewhere in the following years. Similarly, the BTG abandoned the development of all other chelating drugs except L1 and licensed the L1 invention to the generic pharmaceutical company Apotex, Canada, which received regulatory approval from the EU authorities for the use of L1 in 1999, followed by many other countries worldwide and also the USA FDA authorities in 2011, following the intervention of the USA Thalassemia Organization ,105,107.The academic and commercial conflicts regarding the use of L1 continued following the developmental stage and later introduction of DFRA in 2005 by Novartis, which was also the initial and exclusive manufacturer of DF for many years before the introduction of L1 ,110,111.The absence of full formal animal or other pre-clinical toxicology studies in the case of L1 by either Cipla or Apotex pharmaceutical companies has put L1 at a “theoretical disadvantage”, and for that reason it was initially classified as a “second-line” iron-chelating drug in comparison to DF and DFRA ,90,91,92With regards to its safety, long-term studies and continuous clinical monitoring involving thousands of thalassemia and other categories of patients for the last 30 years have confirmed the low toxicity levels of L1 ,120. TheDeferiprone’s ability as a monotherapy or in combination with DF to clear all excess iron and maintain normal iron stores using personalized dose protocols in regularly transfused thalassemia major patients signifies the complete treatment of iron overload and the achievement of the major aim of iron chelation therapy  119,120,122,123.Unlike the discovery and development of deferiprone, which was regarded as a life-saving drug for thousands of iron-loaded patients, especially in developing countries, the development of the maltol–iron complex was not urgently pursued by pharmaceutical companies. The delay was caused by commercial considerations and especially the availability of a large number of competing iron formulations used for the treatment of IDA, a condition generally considered non-life-threatening ,26.The discovery of the maltol–iron complex and its proposed use in IDA originated from the identification in 1979–1982 of the naturally occurring plant product and phytochelator maltol as an alpha-ketohydroxypyrone chelator, which was widely available and used in humans . The selFurther developmental studies involving the in vivo confirmation of the effects of the maltol–iron complex in relation to IDA were conducted following the original studies and design phase of 1979–1982 . These iIn a set of different experiments in rats, increased iron (59-Fe) uptake was observed following the intraduodenal administration of the iron (59-Fe) maltol in comparison to other hydrophilic iron (59-Fe) mixtures with fumarate, gluconate and EDTA . The oraDespite some initial preliminary interest about the development and commercialization of the maltol–iron complex for IDA by pharmaceutical companies, further animal and clinical studies, including long-term toxicology studies, were not pursued, probably because of the overall expenditure required for a new drug’s development at the time. No further efforts for the pharmaceutical development of the maltol–iron complex were undertaken, and the interest was focused on the pharmacological research aspects of maltol and its iron complex and other metal complexes  33,60,1,160,127.Many categories of patients have received the maltol–iron complex in a number of clinical studies, including for Crohn’s disease, ulcerative colitis, chronic kidney disease, pulmonary hypertension and also patients intolerant to other iron formulations ,138,139.There are several other advantages in the use of the maltol–iron complex over other iron formulations, including rapid iron absorption, low toxicity and higher selectivity in iron delivery in comparison to other iron formulations. These advantageous results, cause a decrease in the toxicity associated with the excess non-absorbable iron, which is usually observed with other iron formulations. In addition, the efficacy and low toxicity of the maltol–iron complex could benefit many patients experiencing complications and toxicity with other iron formulations, including intravenous iron and ferrous sulphate ,142,143.The level of safety of the maltol–iron complex appears in general to be satisfactory. This observation has also been reported in almost all of the clinical studies and trials, whereby the maltol–iron complex has been shown to be tolerable and effective, with significant improvements in anemia for the different categories of patients treated. In this context, the most common adverse effect during the clinical studies was mild gastrointestinal intolerance ,131.Overall, the maltol–iron complex may have many general advantages over other iron formulations for the treatment of IDA, which include the ease of administration, low toxicity, short timing for achieving the normalization of hemoglobin levels and low cost. In particular, the low cost of maltol–iron formulations and their general availability are major concerns affecting global health, considering that the vast majority of IDA patients live in developing countries with low health budgets. Furthermore, the low costs of maltol and iron may encourage the development of many different maltol–iron formulations, which could overturn any proprietary and other claims similar to generic pharmaceuticals ,145,146.While the major efforts in the development of L1 and the maltol–iron were based on the treatment of transfusional iron overload and IDA, respectively, their possible applications in other diseases were also suggested and tested at the early stages of their development, thereby contributing important information in the overall pharmacology and toxicology of both of these two drugs.The additional fields of investigation related to these two drugs were broadly based on other diseases of iron metabolism, infectious diseases, conditions related to free radical pathology and metal toxicity conditions other than for iron. In the meantime, many other analogues of L1 and iron–maltol were synthesized and tested for comparison with the original findings. The investigations included in vitro, in vivo and clinical studies.Thousands of patients suffering from iron overload and also other illnesses, as well as normal volunteers, have been treated in the last 40 years with L1, which is regarded as one of the safest drugs in the world per dose, e.g., 50–100 mg/kg received on a daily basis. In this context, the major category of patients receiving L1 is β-thalassemia major patients, followed by many other categories of iron-loaded patients, including β-thalassemia intermedia, HbE β-thalassemia, HbS β-thalassemia, sickle cell anemia, myelodysplastic syndrome, aplastic anemia, Fanconi’s anemia, Blackfan–Diamond anemia, pyruvate kinase deficiency, idiopathic hemochromatosis, iron overload in hemodialysis, and juvenile hemochromatosis ,153,154.Similarly, many other categories of patients with normal iron stores have also been receiving L1, mostly in short- but also in long-term clinical trials. The repurposing of L1 for diseases other than iron overload was organized based on similar dose protocols to those of iron overload and took place originally in the in the UK (RFHSM) but also other countries within a few years of initiating the clinical trials with transfusional iron-loaded thalassemia and myelodysplasia patients ,81,82,83In general, no serious toxicity was reported for clinical trials of up to 9 months duration and with a maximum dose of 100 mg/kg/day in patients with normal iron stores. Most importantly, significant clinical improvements have been reported in most of these categories of patients ,165,166.However, it is unfortunate that in many of the recent clinical trials involving mainly neurodegenerative disease patients, no rationale for the selection of the L1 dose protocol nor of iron metabolism balance studies was given ,159,160.It can be suggested in general that the positive results in terms of safety and the diverse categories of iron-loaded and other patients treated in clinical trials with L1 have increased the prospects of the wider use of the drug in many other diseases, including diseases related to free radical pathology and also in cancer ,172,173.The identification of the possible applications of maltol and the maltol–iron complex in medicine was proposed following their physicochemical characterization, protein and cellular interactions and in vivo and other studies . Within The maltol–gallium complex  has attracted a lot of interest because it has reached the stage of clinical trials and veterinary use, mainly for its anticancer and antimicrobial activities ,180,181.Another major area of application to medicine in relation to iron and other metal complexes of maltol is their use in the theranostic and diagnostic fields, which are rapidly expanding, involving many diseases ,191,192.The increased number of applications of maltol–metal complexes in medicine and veterinary medicine, as well as the pharmacological and toxicological information obtained from relevant studies, has increased the prospect of their wider use in many other fields of diagnostic and theranostic medicine ,198,199There are increasing prospects for the wider application of L1 and the maltol–iron complex in medicine, including for the optimization of existing therapeutic applications involving improved dose protocols, as well as combinations with other drugs or natural products, personalized medicine adjustments, the treatment of more and different clinical conditions and also more diagnostic and theranostic applications. In particular, there are many metabolic pathways and associated diseases that can further be investigated and targeted, with some involving iron interactions and free radical pathologies, many diseases related to metal metabolic pathways and toxicity other than iron, metal supplementation in essential metal ion deficiency diseases and new drug formulations and routes of administration. Many of these new applications have been suggested from relevant in vitro and in vivo studies and also following new clinical evidence ,173,186.The emphasis on new clinical applications of many drugs, including both L1 and the maltol–iron complex, is usually related to orphan diseases and diseases with no effective treatments . In thisExamples of previously established cancer targets include the classical restriction or reduction of the iron supply, inhibition of transferrin iron delivery and inhibition of ribonucleotide reductase in DNA synthesis, the high antioxidant potential by inhibiting free radical formation etc., ,206,207.In contrast to the mode of action of L1 in the above targets, lipophilic chelator metal complexes similar to maltol–iron and also other more lipophilic iron complexes have been proposed for the induction of ferroptosis in cancer cells, especially in cases of refractory or recurring tumors, and also in cases of drug resistance and metastasis  173,188188,204. The prospect of the application of L1 in infectious, inflammatory and many other diseases in addition to cancer has been previously reviewed ,183,184.Neisseria meningitides or cancer types such as glioblastoma, both of which depend on iron supply for growth [In general, the characteristics of the targets can impose many limitations in the selection of therapeutics, including chelating drugs for the optimization of treatments. For example, only L1 from all three iron-chelating drugs  can cross the blood–brain barrier and target infections in the brain, such as meningitis caused by r growth ,20,173.There are many other areas of potential development and applications of L1 and maltol–iron complexes. For example, intravenous L1 and maltol–iron complex formulations may have to be designed to benefit cancer and other categories of patients unable to receive oral formulations ,234,235.Despite the many difficulties and controversies, L1 and the maltol–iron complex are prime examples of academic drug discovery and orphan drug development medicinal products. In particular, L1 has helped in the treatment and survival of hundreds of thousands of iron-loaded and other patients worldwide in the past 30 years. Similar results are expected from the use of the recently approved maltol–iron complex for the treatment of IDA, which affects 1 in 3 or 4 individuals worldwide.The repurposing of L1 in many categories of non-iron-loaded patients, including neurodegenerative, infectious, inflammatory, metal toxicity and other conditions, signifies the safety and multitargeting potential of the drug. Similarly, the use of the maltol–gallium complex in cancer and also of other maltol–metal complexes in other therapeutic, theranostic and diagnostic applications highlights the future routes of development and use of new therapeutic, theranostic and diagnostic maltol and other chelator metal complexes.New advancements in the pathology of free radicals, cancers and many other diseases, including the discovery of new iron and other metal metabolic routes and proteins that can be modulated by L1, maltol–iron and also other new chelators and metal complexes, underlines the importance of chelators and chelator metal complexes in medicine. In particular, their use as monotherapies or in combinations with other drugs is essential for the improvement of the treatment of many diseases and increased prospects of patients’ survival, especially in many diseases with no effective therapies.


Abnormal deposition of extracellular matrix (ECM) in lung tissue is a characteristic of idiopathic pulmonary fibrosis (IPF). Increased collagen deposition is also accompanied by altered collagen organization. Collagen type XIV, a fibril-associated collagen, supports collagen fibril organization. Its status in IPF has not been described at the protein level yet. In this study, we utilized publicly available datasets for single-cell RNA-sequencing for characterizing collagen type XIV expression at the gene level. For protein level comparison, we applied immunohistochemical staining for collagen type XIV on lung tissue sections from IPF patients and compared it to lung tissue sections from never smoking and ex-smoking donors. Analyzing the relative amounts of collagen type XIV at the whole tissue level, as well as in parenchyma, airway wall and bronchial epithelium, we found consistently lower proportions of collagen type XIV in all lung tissue compartments across IPF samples. Our study suggests proportionally lower collagen type XIV in IPF lung tissues may have implications for the assembly of the ECM fibers potentially contributing to progression of fibrosis. Currently, the median survival time of patients with IPF is less than for many cancers, and there is no available cure1. As the lung ECM structure in IPF is drastically altered and provides a feedback loop that perpetuates disease progression3, investigating the underlying matrix pathology is expected to improve our understanding of the disease.Idiopathic pulmonary fibrosis (IPF) is the result of aberrant deposition of extracellular matrix (ECM) in the alveolar septa, causing restricted breathing in patients5. Among other types of collagens, collagen type XIV (COL14) is a fibril-associated collagen with interrupted triple-helices (FACIT)6 which consists of two collagenous domains (COL1 and COL2), which are important for the formation of the COL14 triple helical structures and for the binding to other fibrillar collagens, and three non-collagenous (NC) domains 7. Roles for COL14 have been suggested in regulation of fibrillogenesis, cell proliferation and differentiation9. The absence of COL14 in mice resulted in dysregulated biomechanical properties of the skin and altered fibril formation in the tendon6. Culture of human skin and mouse 3T3 fibroblasts on immobilized COL14 showed that COL14 inhibits cell proliferation and triggers the differentiation of 3T3 fibroblasts8. The presence of COL14 has been demonstrated previously in several tissues including skin, tendon, cornea and lung; especially in the vicinity of the blood vessels, airway smooth muscle cells (ASM) and bronchial epithelium10. In previous studies by Nishiyama et al.11 and Gordon et al.12, a role for COL14 in the regulation of mechanical stress has been suggested. We have previously reported the localization of COL14 in regions that would be subjected to high mechanical stress in the lung including the parenchymal region, blood vessels, ASM and bronchial epithelium10. Therefore, the presence or absence of COL14 could impact the fibrillogenesis and organization of the collagen type I fibrils and the biomechanical properties of the ECM in different lung compartments and subsequently the lung function.Deposition of collagens in the altered ECM in IPF has been well documented, including an increase in collagen types I and III, as well as changes in the organization of collagen fibrils13. However, the time for development of fibrosis in this model compared to IPF and/or species differences can influence how these results translate to humans. Accordingly, in the current study we aimed to investigate whether there are differences in the COL14 gene expression and protein levels in lung tissue from patients with (end stage) IPF compared to normal human lung tissue.Unlike abnormal collagen (type I) deposition and organization in IPF which has been described in detail, the role of FACITs in this process or, more specifically, involvement of COL14 in IPF, remains unknown. Previously, in a mouse model of fibrosis, higher levels of COL14 deposition were shown in bleomycin-treated mice compared to control miceCOL14A1 was analyzed in lung tissue of patients with IPF and non-IPF donors using publicly available single-cell RNA sequencing datasets from the Human Lung Cell Atlas (HCLA) consortium and the IPF atlas dataset from Adams et al.15. These datasets were analyzed and clustered using HCLA consensus cell-type annotations for 4 major cell groups: endothelial, epithelial, immune and stromal cells for analysis of the expression profile of the Collagen Type XIV Alpha 1 Chain (COL14A1) gene which encodes COL14 protein.Cell-type specific gene expression of 10.IHC was used to quantify proteins of interest in lung tissue. Control lung tissues were obtained through resections from patients undergoing surgery for lung cancer, taken from as far away from the tumor region as possible and were macroscopically normal tissue as assessed by pathologists. Fibrotic lungs were obtained from explanted material following transplantations Table . Formalihttps://umcgresearch.org/w/research-code-umcg) and national ethical and professional guidelines ). Lung tissues used in this study were derived from leftover lung material after lung surgery and transplant procedures. These materials were not subject to the Medical Research Human Subjects Act in the Netherlands as confirmed by a statement of the Central Ethics Review Board of the University Medical Center Groningen; all biological samples are from archival materials that are exempt from consent in compliance with applicable laws and regulations  art 458/GDPR art 9/UAVG art 24). All samples and clinical information were coded before experiments were performed, blinding any identifiable information to the investigators.The study protocol was consistent with the Research Code of the University Medical Center Groningen  in the whole tissue of non-IPF and IPF lung samples using the same image analysis pipeline Fig. . CompariCollectively, our results show proportionally lower COL14 protein expression relative to other ECM components that make up lung tissue in patients with IPF compared to both ex-smoker and never-smoker non-IPF controls. To the best of our knowledge, this is the first report of protein level changes related to spatial location of COL14 in human lung tissue in IPF. In addition, we found a lower ratio of COL14 to COL1 in IPF lungs compared to never smoker non-IPF controls.16 suggests that such an absolute increase is likely. However, the ratio of COL14 to COL1 in the same study was lower in IPF lungs compared to control lungs, which is consistent with our findings. While an early study analyzing the amount of COL14 in IPF lungs semi-quantitatively reported higher COL14 in established fibrotic areas and lower COL14 in fibroblastic foci17, these results portray an absolute amount of protein rather than relative to other ECM components as depicted in our study.In this study, we examined the proportion of lung tissue positive for COL14 in each sample and not the absolute amount of protein. As the total amount of tissue present in IPF lung sections is larger than in controls, it is conceivable there is an increase in absolute amount of COL14, while the proportion of COL14 in comparison to other ECM components is reduced. A previous report of higher mass spectrometry counts of COL14 in IPF lungs compared to non-IPF lungs9 to investigate the changes in COL14A1 expression in lung tissue from patients with IPF compared to non-IPF controls have revealed a higher expression in fibroblasts and myofibroblasts, as well as in basal cells isolated from IPF lungs. These differences in COL14A1 mRNA expression between patients with IPF and controls are in the opposite direction than the differences observed at the protein level in our IHC stainings. It has been shown previously that correlations between the steady-state number of protein molecules per cell and their associated mRNA molecules are weak18. Proportional changes between the relative abundances of the proteins and the relative abundances of the mRNA of these proteins is also not guaranteed19, and possible mechanisms for this lack of proportion between mRNA and protein levels have been discussed elsewhere20. In addition, the status of the proteins already deposited in the ECM is unlikely to be determined by their mRNA. It might be possible that the increased gene expression of COL14A1 reflects an attempt of the structural cells of the lung to compensate for the reduced COL14 protein levels observed in lung tissue.The single-cell analyses using the IPF atlas21. Even with this, recent proteomics data from Hoffman et al. show a lack of absolute increase in COL1A1 in decellularized IPF lung samples22. An interesting observation from our study was the influence of smoking on the lung ECM proteins in the lungs of non-IPF donors. While relative amounts of COL14 did not differ based on the smoking status of the non-IPF controls, the percentage positively stained areas for COL1 differed significantly between the never smoker and ex-smoker groups. Considering that the lungs of ex-smoker donors did not have visible fibrotic regions, it is possible that this higher relative amount of COL1 reflects more absolute amounts. In IPF lung tissue, the samples had COL14 positive areas in dense fibrotic tissue while the fibroblastic foci and honeycomb regions were mostly devoid of COL14. Further research is needed to investigate how the collagen organization differs in these dense fibrotic tissue areas with respect to the COL14 presence as well as relating these changes to lack of COL14 in fibroblastic foci or honeycomb regions.Regarding our results from the COL1 image analysis, we did not observe a relative higher amount of the percentage positively stained areas in IPF lung samples compared to control groups. This lack of increase, however, does not mean a lack of absolute increase as more deposition of COL1 in IPF lungs has been previously established5. More research correlating fibrillar collagen organization with FACITs such as COL14 will increase understanding of the involvement of COL14 in the development and/or progression of fibrotic responses. A recent study using mice deficient in COL14A1 found increased stiffness and abnormal collagen fibril organization in the corneas of COL14A1-knockout mice compared to wildtypes23. These observations parallel well-documented increases in the stiffness of lungs from patients with IPF16. Together with our observations reported here, it is tempting to speculate that COL14 protein levels in IPF lungs do not mirror the increase in other ECM proteins in lung tissue during fibrosis, thereby leading to more disorganized collagen fibers with higher stiffness in lungs of patients with IPF.How COL14 is involved in the regulation of human lung ECM structure and how changes in its proportional expression influence fibrotic responses in IPF is currently unknown. As FACITs regulate the structural organization of fibrillar collagens, it can be argued that lower proportions of COL14 in IPF lungs contribute to the reported imbalance between organized and disorganized fibrillar collagen in IPFSupplementary Information.


Neglected tropical diseases (NTDs) are a major public health burden which mainly affects poor populations living in tropical environments and hard-to-reach areas. The study sought to examine coverage of preventive efforts, and case surveillance for NTDs in hard-to-reach communities in Ghana.The study investigated treatment efforts for lymphatic filariasis (LF), and onchocerciasis and schistosomiasis/soil transmitted helminths (SCH/STH) at household level, in difficult-to-access communities in Ghana. A total of 621 households were sampled from 6 communities in the Western, Oti and Greater Accra regions.Over 95% of the households surveyed were covered under mass drug administration (MDA) campaigns for lymphatic filariasis (LF) and onchocerciasis. More than 80% of households had received at least two visits by community drug distributors under the MDA campaigns in the last two years preceding the study. In addition, over 90% of households in the LF and onchocerciasis endemic communities had at least one member using anthelminthic medications under the MDA campaigns in the 12 months preceding the study. However, households where no member had taken anthelminthic medications in 12 months preceding the study were over 6 times likely to have someone in the household with LF.This study determined that SCH/STH, LF and onchocerciasis are of serious public health concern in some communities in Ghana. There is an urgent need for holistic practical disease control plan involving both financial and community support to ensure total control of NTDs in difficult-to-access communities is achieved.The online version contains supplementary material available at 10.1186/s12889-023-16652-1. Neglected tropical diseases (NTDs) are a major public health issue affecting poor populations living in tropical environment, and hard-to-reach areas , 2. AccoIn Ghana, unsafe health practices, limited access to safe water, poor sanitation, and a lack of awareness of the causes of NTDs continue to pose a serious challenge to achieving elimination of NTDs , 7. NoneAnopheles gambiae mosquitoes infected with the LF parasite (Wuchereria bancrofti) in communities where transmission is supposed to have been interrupted [Onchocerca volvulus in Simulium damnosum has been found in some communities where transmission is supposed to have been disrupted [Although progress has been made to reduce the burden of selected NTDs in Ghana , 14, howerrupted . Similarisrupted . In addiisrupted . Studiesisrupted . The success of NTD control programs relies on reducing pockets of disease transmission countrywide . As suchThese reasons underscore the need for studies that examine control efforts in at-risk populations in order to reduce the burden and control NTDs such as LF, onchocerciasis, and SCH/STH in Ghana . This stThe study was cross-sectional in design assessing interventions to control LF and onchocerciasis using a household survey among people living in difficult-to-access communities in Ghana.Data on LF were collected in two communities in the Western Region of Ghana – Old Bakanta and New Bakanta (both in the Ellembelle District). The study sites for onchocerciasis were Azua and Wui in the Nkwanta North District of the Oti Region. Data on SCH and STH were collected in Tuanikope and Pediatorkope in the Ada East District of the Greater Accra Region Fig. . These cIn each community, all households were eligible to be selected to take part in the survey. The total number of households in each community ranged between 60 and 250, depending on the size of the community. A simple random sampling approach was used to select households to participate in the study from May 2019 to September 2019. Estimated sample size was calculated based on the following: margin of error = 5%; design effect = 1; clusters = 1; confidence level = 95%. The combined sample size was 621 households. Table A household-level questionnaire was administered to heads of households (or the oldest adult household member) in the study communities  of the College of Health Sciences, University of Ghana . Written informed consent was provided by all adult participants.Univariate results were expressed as percentages  or means ± standard deviations (for continuous variables). Logistic regression analysis was used to assess the association between preventive measures and the prevalence of LF and onchocerciasis. The data were analysed with SPSS (version 23).Table The median monthly household income ranged from GHC150 (≈$27) in Azua, to GHC350 (≈$63) in Wui. The average household size was 5.8, although in the community of Azua, the average household size was higher (7.3)  of the respondents reported that water for the household use was from unprotected sources (such as surface water and borehole). All other household heads (45%) reported that water for their household use was from protected sources (such as pipe in the house or public tap/standpipe). More than half of household heads (53%) reported lack of a toilet facility, and indicated that members of the household as a result practiced open defecation.Approximately 96% and 98% of households in the LF and onchocerciasis endemic communities were covered under MDA campaigns Table . FurtherIn addition, 90% and 95% of households in the LF, and onchocerciasis endemic communities had at least one member using anthelminthic medications under the MDA campaigns in the 12 months preceding the study Table . In the Table Adjusted odds ratio analyses revealed that households where no member had taken anthelminthic medications in the 12 months preceding the study were over 6 times more likely to have someone in the household with LFLymphatic filariasis (LF), onchocerciasis, schistosomiasis, and soil transmitted helminths are important neglected tropical diseases in sub-Saharan Africa, including Ghana. This study investigated treatment efforts for lymphatic filariasis (LF) and onchocerciasis at the household level in difficult-to-access communities in Ghana. Findings from this study revealed households where no member had taken anthelminthic medications in the 12 months preceding the study were over 6 times likely to have someone in the household with LF, and self-reported household prevalence for onchocerciasis was higher compared to LF and SCH/STH. This finding corroborates the assertion that even though a combination of effective vector control and access to treatment will reduce the prevalence of LF in communities, MDA is a more effective control strategy . This stThis study revealed that the majority of households covered under preventive treatment for LF and onchocerciasis had received at least two MDA visits in the last two years preceding the study and had at least one household member using anthelminthic drugs within the last year preceding the survey. On the contrary, there had been no MDA visits in the SCH/STH endemic communities in the last two years preceding the survey, and only 5% of households reported using anthelminthic drugs in the last year. These findings suggest that control strategies for NTDs have been unequal in difficult-to-access communities in Ghana. In addition, it has been suggested that to help control NTDs, there should be sustained, expanded, and extended drug access programs to ensure the necessary supply of drugs, as well as addressing identified drawbacks to improve the effectiveness of other interventions . StudiesHowever, taking into account the logistical challenges associated with MDA and other vector control interventions, achieving coverage of the entire population is hardly ever achieved, particularly in difficult-to-access communities, and this results in residual infections . TherefoThe implementation of semi-annual community-wide MDA in the SCH/STH endemic study communities should be vigorously pursued and sustained. Evidence from previous studies in similar settings show that MDA programs have been largely effective against SCH and STH particularly among school-age children , 25.Optimizing surveillance, and improving the success rates of the MDA and other vector control programs in Ghana depends in large part on visits facilitated by CDDs. The findings suggest that CDDs in communities where NTDs are endemic should be given well-defined mandates, regularly trained, and supervised, and given the necessary resources to execute their mandate considering the relative precarious circumstances in the communities they serve. Over time, this will guarantee the success of strategies to control and possibly eliminate NTDs in difficult-to-access communities.Additional file 1: S1. File Household Questionnaire-2.


Background and aims: Patients frequently have concerns about their disease and find it challenging to obtain accurate Information. OpenAI’s ChatGPT chatbot (ChatGPT) is a new large language model developed to provide answers to a wide range of questions in various fields. Our aim is to evaluate the performance of ChatGPT in answering patients’ questions regarding gastrointestinal health. Methods: To evaluate the performance of ChatGPT in answering patients’ questions, we used a representative sample of 110 real-life questions. The answers provided by ChatGPT were rated in consensus by three experienced gastroenterologists. The accuracy, clarity, and efficacy of the answers provided by ChatGPT were assessed. Results: ChatGPT was able to provide accurate and clear answers to patients’ questions in some cases, but not in others. For questions about treatments, the average accuracy, clarity, and efficacy scores (1 to 5) were 3.9 ± 0.8, 3.9 ± 0.9, and 3.3 ± 0.9, respectively. For symptoms questions, the average accuracy, clarity, and efficacy scores were 3.4 ± 0.8, 3.7 ± 0.7, and 3.2 ± 0.7, respectively. For diagnostic test questions, the average accuracy, clarity, and efficacy scores were 3.7 ± 1.7, 3.7 ± 1.8, and 3.5 ± 1.7, respectively. Conclusions: While ChatGPT has potential as a source of information, further development is needed. The quality of information is contingent upon the quality of the online information provided. These findings may be useful for healthcare providers and patients alike in understanding the capabilities and limitations of ChatGPT. Gastrointestinal (GI) complaints and symptoms account for approximately 10% of all general practice consultations  and are AI chatbots employ deep learning-based natural language processing (NLP) that evaluates natural human language input and replies accordingly in a conversational mode . These mThe recent release of OpenAI’s ChatGPT in November 2022  has garnThe effectiveness of large language models in answering patients’ questions in the field of gastroenterology has not yet been thoroughly evaluated. In this paper, we aim to evaluate the performance of OpenAI’s ChatGPT chatbot in answering patients’ questions concerning gastrointestinal (GI) topics. This evaluation will focus on several key areas, including the accuracy and clarity of the information provided, the ability of the model to handle a wide range of questions, and the overall effectiveness of the model in addressing patients’ concerns and providing them with the information they need to make informed decisions about their health.Our evaluation aims to provide insights into the capabilities and limitations of large language models in answering patients’ questions in various gastroenterology subjects. Ultimately, our goal is to contribute to the ongoing development of large language models and their use in the field of gastroenterology, with the aim of improving the quality of care and information available to patients.To evaluate the performance of the newly- released large language model, OpenAI’s ChatGPT chatbot, in answering patients’ GI-related questions, we conducted a comprehensive study using a representative sample of real-life questions from patients in this field. The study was designed to assess the accuracy and clarity of the information provided by the chatbot, as well as its overall effectiveness in addressing patients’ concerns and providing them with the information they need to make informed decisions about their health.The study sample consisted of 110 real-life questions from patients in the field of gastroenterology, gathered from open internet sites providing medical information to diverse patients’ questions. These questions were selected to cover a wide range of topics, including common symptoms, diagnostic tests, and treatments for various gastrointestinal conditions. The questions were selected to reflect the types of questions typically asked by patients in gastroenterology and to provide a representative sample of the types of questions that the chatbot would encounter in a real-world setting.The questions were provided to the OpenAI chatbot and the answers were recorded. The answers provided by the chatbot were then assessed in consensus by three experienced gastroenterologists, each with more than 20 years of experience. All gastroenterologists work in a tertiary medical center, as well as in community clinics, and together cover all sub-specializations of gastroenterology: IBD experts, motility, hepatology, nutrition, and advanced endoscopy.The physicians graded each chatbot answer according to a scale of 1–5  in 4 categories: accuracy, clarity, up-to-date knowledge, and effectiveness in a consensus agreement between all three gastroenterologists. Since the questions were divided according to specific topics—common symptoms, diagnostic tests, and treatments—results are shown in a separate table for every topic. (Python (Ver. 3.9) was used for all statistical calculations. The average score ± standard deviation (SD) was calculated for each category and is shown in a table. A distribution graph of the answer grades for all groups by answer category was plotted. A Kruskal–Wallis one-way analysis of variance was used to determine the statistical difference between the groups.Overall, 110 various typical patient questions were presented to the OpenAI chatbot. Forty-two included various questions regarding treatment options in diverse gastroenterology fields. Questions were chosen to include the whole spectrum of specification from very specific questions  to wider questions not referring to definite disease staging or severity . All questions chosen were short and clear for better standardization. The results of the evaluation for the treatment questions are shown in A full list of all questions and answers is presented in the Overall, the OpenAI chatbot answers to the questions dealing with treatment options varied wildly between the different topics and were inconsistent in their level. Notably, at the end of almost all the answers, the patient is referred to a doctor/healthcare provider for further evaluation.The results of the evaluation for questions related to symptoms are shown in The results of the evaluation for questions related to diagnostic examinations are shown in Diversity in the quality of answers to the diagnostic examination was the highest of all groups. While many answers were correct and informative, other medical terms were simply not recognized by the chatbot .As shown graphically in p = 0.019) and up-to-date (p = 0.009), but not for the subjects of clarity (p = 0.071) and efficacy (p = 0.071).Statistical difference between the groups was shown for the subjects of accuracy (Overall, our study provides a comprehensive evaluation of the performance of a large language model, OpenAI’s ChatGPT chatbot, in answering patients’ questions in the field of gastroenterology. The results of the study will hopefully be valuable for healthcare providers and patients alike, as they will provide important insights into the capabilities and limitations of these models in providing accurate and reliable information about gastrointestinal health.Generally, the results of our evaluation of OpenAI’s ChatGPT large language model, as a potential tool for answering patients’ GI-related questions, are concerning. Despite the impressive capabilities of this model in other applications, our study found that it was insufficient for reliably answering patients’ questions in this domain.In our study, we presented the model with a range of common gastroenterological questions and assessed its ability to provide accurate and helpful responses. While the model could generate responses for all questions, the accuracy and helpfulness of these responses varied significantly. In many cases, the model’s responses were either incomplete or entirely incorrect, indicating a lack of understanding of the subject matter.These findings are particularly concerning given the importance of accurate information in the medical field. Patients often rely on Internet information to make decisions about their health and well-being, and inaccurate information can have serious consequences. As such, it is essential that any tool used to provide medical information to patients be able to provide accurate and reliable responses.Interestingly, while the answers to treatment-based questions and symptom-based questions showed a similar and relatively steady quality and effectivity , diagnosFurthermore, our study also highlighted the limitations of OpenAI’s ChatGPT chatbot in the medical domain. The ability to understand and accurately respond to complex medical questions requires a deep understanding of the subject matter, as well as the ability to process and integrate information from a variety of sources . While COur results are in line with previous data assessing other artificial intelligence conversational agents in healthcare ,7,11. AsRecent data from the last months suggest that LLMs hold the potential for significant impacts in medicine ,13.In our previous work, we examined the utility of ChatGPT in identifying top research questions in gastroenterology. Our conclusion was that ChatGPT may be a useful tool for identifying research priorities in the field of GI, yet we noted the need to improve the originality of the research questions identified .In telehealth, LLMs such as ChatGPT could improve efficiency and scalability, and provide unbiased care . DespiteSignificantly, it is worth mentioning that all of these studies have been published within the recent months subsequent to the initial release of the inaugural version of ChatGPT. This accumulation of research findings attests to the remarkable potential impact and significance that ChatGPT holds for the field of medicine in the foreseeable future.Our study had a few limitations. First, the choice of questions naturally influenced the answers obtained by the OpenAI chatbot. However, the wide variety of questions and their relatively high number minimized the chance for bias. Furthermore, the answers were graded with the consensus of three physicians; there is a possibility that other physicians might have had a different point of view. Nevertheless, to minimize that risk, we chose highly experienced gastroenterologists with wide clinical experience and more than 70 years of practicing gastroenterology both in a tertiary medical center and in community practice. Lastly, there were no comparisons with other chatbots to gauge the relative merits of ChatGPT against other similar technologies, and no blinded comparison between human and chatbot answers was performed. These research directions necessitate further dedicated exploration to explore and investigate its potential in greater detail.Importantly, our study did not include patients’ comments and, therefore, is not valid in terms of assessing patients’ points of view. This merits further specific research.Overall, our study suggests that caution should be exercised when considering the use of a large language model, such as OpenAI’s ChatGPT, for providing medical information to patients. While the model has the potential to be a powerful tool, it is not yet ready to be relied upon for this critical task. Further research and development are needed to improve its capabilities in the medical domain before it can be used with confidence.