Actinic keratoses: Erythematous scaly lesions on sun-damaged skin & considered “precancerous” lesions that have the potential to progress into invasive SCC.
Bowen’s disease: SCC in situ It has the potential to progress to invasive SCC.
Leukoplakia: Leukoplakia refers to a white patch or plaque on the oral mucosa that cannot be wiped off and cannot be characterized clinically or pathologically as any other disease.
Hereditary disorder of keratinization characterized by expanding atrophic anular patch(es) surrounded by prominent keratotic ridge called the cornoid lamella
They are a heterogenous group of inherited disorders of epidermal differentiation featuring excessive scaling, Ichthyosis vulgaris,
X-linked recessive ichthyosis,
Lamellar ichthyosis,
Non-bullous ichthyosiform erythroderma,
Bullous ichthyosiform erythroderma,
Ichthyosis bullosa of Siemens,
Harlequin ichthyosis
This lecture reviews the role of laser therapy in dentistry in particular for Periodontal treatment. Dr. Smith reviews many of his own cases with the audience.
Please contact Dr. Smith with questions.
drsmith@cpident.com
Actinic keratoses: Erythematous scaly lesions on sun-damaged skin & considered “precancerous” lesions that have the potential to progress into invasive SCC.
Bowen’s disease: SCC in situ It has the potential to progress to invasive SCC.
Leukoplakia: Leukoplakia refers to a white patch or plaque on the oral mucosa that cannot be wiped off and cannot be characterized clinically or pathologically as any other disease.
Hereditary disorder of keratinization characterized by expanding atrophic anular patch(es) surrounded by prominent keratotic ridge called the cornoid lamella
They are a heterogenous group of inherited disorders of epidermal differentiation featuring excessive scaling, Ichthyosis vulgaris,
X-linked recessive ichthyosis,
Lamellar ichthyosis,
Non-bullous ichthyosiform erythroderma,
Bullous ichthyosiform erythroderma,
Ichthyosis bullosa of Siemens,
Harlequin ichthyosis
This lecture reviews the role of laser therapy in dentistry in particular for Periodontal treatment. Dr. Smith reviews many of his own cases with the audience.
Please contact Dr. Smith with questions.
drsmith@cpident.com
Abin Abraham Mammen.
Background: Trigger point is a extremely irritable local spot of exquisite tenderness in the nodule
within the tangible taut muscle band. The prevalence studies have shown that the occurrence of myofascial trigger point in the general population.
Objective: The aim of the study was compare the effects of low level laser therapy( LLLT) Vs
ultrasound therapy in the management of active trapezius trigger point.
Methodology: The participants will be allocated into two groups using simple random sampling.
One group has to be given Low level laser therapy (LLLT) and Moist Heat and other group treated
with US and Moist Heat. Both group receive treatment for 3 times a week. Total number of 9
session has to be given in 21 days. The outcome measure has to be taken at the first day and end
of the day.
Conclusion: Based on the above results we conclude that Low Level Laser Therapy can be used as a therapeutic device in the management of Active Trapezius Trigger points.
Those who administer ionizing radiation must become familiar with the magnitude of exposure encountered in medicine, dentistry and every day life; the possible risks associated with such exposure; and the methods used to affect exposure.
Practitioners should remain informed about safety updates to further improve diagnostic quality of radiographs and decrease radiation exposure.
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Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
3. Questions
• Is there a need for laser treatment ?
• Is it effective ?
• Is it proven ?
• Which parameters ?
• Is it economically reasonable ?
Review of evidence
4. • Is there a need for laser treatment ?
• Is it effective ?
• Is it proven ?
• Which parameters ?
• Is it economically reasonable ?
Questions
Review of evidence
5. Toe Fungus Alternate Treatment
Options
• Poor current treatment alternatives
– Daily lacquer ---10% success rate
• Requires ~1 year of application to achieve 10% success rate
• Low cost but low success
– Oral medication (Lamisil & Sporanox) -- 50% success rate
after 6 – 9 month program
• High liver stress
• Cannot repeat drug therapy if it does not work
• Single active agent is not always effective in all types of fungus
• Interaction with medication
• Contraindicarion in many immunologic and other diseases
6. The need for new therapeutic options
• To minimalize side effects
• Confine only to affected area
• Treatment options for patients with liver disease and
multimorbidity
• Inability to develop microbial resistance
• Lack of mutagenic and genotoxic effects
Why are lasers attractive?
7. Questions
• Is there a need for laser treatment ?
• Is it effective ?
• Is it proven ?
• Which parameters ?
• Is it economically reasonable ?
Review of evidence
8. Studies on laser treatment effectivness
in onycomycosis
in vitro in vivo
Vural et al.
Manevitch et al.
Aguilar et al.
Bornstein et al.
Harris et al.
Manevitch et al.
Aguilar et al.
Kozarev et Vizintin
Hochmanet al.
Landsman et al.
Weiss
9. The effects of laser irradiation on
Trichophyton rubrum growth.
Vural, E., et al. (2008) Lasers in medical science, 23(4), 349–353.
IN
VITRO
STUDY
10. Laser systems proven ineffective on
T. rubrum growth inhibition
Laser system Wavelength
(nm)
Fluence
(J/cm2)
IPL (Lumenis, Vasculight) 695 - 1000 38, 45, 57
IPL (Lumenis, Vasculight) 795 - 1000 38, 45, 57
Pulsed dye laser (Candela, SleroPlus) 585 8, 11, 14
Erbium YAG laser (Sciton Model Contour) 2940 25
KTP laser (Laserscope, Aura) 532 2, 4, 6, 8
Vural, E., et al. (2008) Lasers in medical science, 23(4), 349–353.
Propably Thermal damage
plays secondary role
11. Q-switched Nd:YAG of 532 and 1064 nm
wavelengths and 4 – 8 J/cm2 fluencies
Laser systems proven effective on
T. rubrum growth inhibition
CONCLUSION:
Nanosecond pulses
of irradiation
Vural, E., et al. (2008) Lasers in medical science, 23(4), 349–353.
Microcavitation Acoustic shock
Thermal shock
T. rubrum cell
Xanthomeganin
(absorbs 532 nm)
Melanin
(absorbs 1064 nm)
12. The Direct Antifungal Effect of 800 nm
Femtocecond Laser on T. rubrum
IN
VITRO
STUDY
Methods:
Strain identification
Culture samples
To verify fungal
infection
SEM NAIL
EXAMINATION
2-4
weeks
CONTROL
Sabuard +
cyclohexamide
SUBCULTURE
Manevitch, Z., et al. (2010) Photochemistry and photobiology, 86(2), 476
13. Laser used in Manevich et al. study:
Ti:Sapphire, femtosecond infra-red laser (MIRA
900, Coherent Radiation, Santa Clara, CA)
800 nm,
200 fsec pulses,
76 MHz frequency
– 800 nm allows to effectively transverse the nail and
is effective at any level
– Good therapeutic index due to difference in fluences
• 4.8 x 1022 photons /s*m2 was effective,
• 17 x 1022 photons /s*m2 was destructive
IN
VITRO
STUDY
Manevitch, Z., et al. (2010) Photochemistry and photobiology, 86(2), 476
CONCLUSION:
14. T. Rubrum
colonies
Nd:YAG
1320 nm
4 J/cm2
vacuum or
cooling
treatment
No Effect of vacuum and thermal shock
on laser treatment of T. rubrum
IN
VITRO
STUDY
Aguilar et al. Proc. of SPIE Vol. 7548 754805-7
1. Laser irradiated samples showed reduced colony
growth compared to untreated samples
2. Vacuum or cooling had little or no effect on
previously irradiated samples
CONCLUSION:
15. In vitro studies
Vural et al.
Q-switched Nd:YAG laser 532
nm and 1064 nm wavelengths
Inhibition of fungal
colony growth
Manevitch et al.
Femtosecond infrared
titanium sapphire, 800 nm
Complete clearance
of T.rubrum infected
nail clippings
Aguilar et al.
Q-switched Nd:YAG laser,
1320 nm by vacuum and
thermal shock
Inhibition of T.
rubrum colony
growth
Bornstein et al.
Diode, 870/930 nm
4074 – 4500 J/cm2
Complete clearance
of T. rubrum and
C.albicans
17. Background - Nail Anatomy
• Fingernails grow ~ 3 mm / month
– Takes 6 months for nail to grow
out
• Toenails grow ~ 1 mm / month
– Takes 12-18 months for nail to
grow out
• Diseased nails tend to grow
slower then normal
18. Treatment of nail fungus
Type of nail fungus pattern:
Subungual and or nail bed
Therapy by thermolysis needs
maximum temperature in
fungus layers
(for effectivity)
and
Minimal temperature in
uninvolved tissue
(increases saftey , reduces
pain)
Onycho-
gryphosis
Nerves
Laser
Capillaries
Courtesy PinPointe
20. Laser used:
1. COOLTOUCH
• Nd:YAG Q switched laser
• 1064 or 1320 nm wl
• 6-350 microsec
• 4mm beam diameter
• Fluence 4 J/cm2
• 50 ms pulse envelope
IN
VITRO
STUDY
21. Reaches Target Temperature
• Move the hand piece over the nail in different directions until the
target temperature is reached
• Real time temperature is displayed
• System will deliver cryogen spray when the set target
temperature is reached
• Adjust target temperature to achieve a comfortable treatment for
the patient
Number of Passes
• Repeat until all the nails have been treated to the target
temperature 2 times
Treatment Interval
• Every 2 - 6 weeks for a total of 3 to 4 treatments,depends on
condition of the nail, clinical response to treatment and rate of
nail growth
22. CoolBreeze 1064nm Laser Treatment
Photos courtesy of Ritchie Steed, DPM
6 weeks Post - TreatmentPre - treatment
23. Post Treatment, 7.5 months
CoolBreeze™ 1320nm Laser Treatment
Photos courtesy of Ritchie Steed, DPM
6 weeks Post - TreatmentPre - treatment
24. • Diode Laser
• Low power
• Requires the use of toe clips
• Treats 4 toes simultaniously
• Protocol requires three 6 min
procedures
Noveon (Nomir Technologies) Laser
25.
26. Noveon (Nomir Technologies) Laser
Bornstein, E., et al. Photochemistry and photobiology, 85(6), 1364–74.
Study
In vitro
Bornstein et al.
In vivo
Landsman et al.
Laser system Noveon, diode, 870/930 nm Noveon, diode, 870/930 nm
Power output
(W) 11,0 3,0
Energy fluence
(J/cm2)
4500
Over 720 sec
204 + 424
Over 120 + 240 sec
Total energy
used in protocol 7920 J 360 + 750 J
Outcome 100% Clearance
38% negative cultures
after 3 x 6 min Tx
Landsman, A. S., et al. (2012) JAPMA, 102(2), 169–171.
IN
VIVO
STUDY
27. Laser treatment for toenail fungus
with PinPointe FootLaser
IN
VIVO
STUDY
Harris, DM, et al. (2009) Proceedings of SPIE, 7161, 71610M–71610M–7.
3 months follow-up
79% (11/14) had over 3 mm of clear
nail growth in 90 days
LR
14 patients
NO -TxTx
28. Laser specifications
IN
VIVO
STUDY
Harris, DM, et al. (2009) Proceedings of SPIE, 7161, 71610M–71610M–7.
Laser used: PinPointe FootLaser, Patholase,
Nd:YAG pulse laser, 1064nm wl
Approved by FDA, CE Mark
Sigle treatment required
CONCLUSION:
Small sample size, (N=14)
There was no culture after treatment
Effectiveness is measured by „clear” nail growth
29. Unique Pulse Modulation
• The PinPointe FootLaser’s
unique combination of
wavelength and pulse
structure for targeting the
fungus
• Laser pulse ends before there
is damage to surrounding
tissue-or pain to the patient
• Other Nd:YAG lasers can be
very painful due to non-
specific pulse modulation
LASER
PRESETS
P1 P2 P3
PULSE
ENERGY
200 mJ 200 mJ 200 mJ
REPETITI
ON RATE
20 Hz 30 Hz 30 Hz
LASER ON
TIME PER
BURST
½ second ½ second 1/3
second
LASER
OFF TIME
PER
BURST
½ second 1/6
second
1/3
second
30. 95% of negative cultures after 3
months and 100% after 6 months.
Laser treatment for toenail fungus
with Dualis (Fotona) Laser
During each treatment visit:
3 treatment visits
12 month folow-up
No sideffects
RESULTS:
IN
VIVO
STUDY
Kozarev, J., & Vižintin, Z. (2010) J Laser Health Academy, 1(1), 1–8
31. Fotona Dualis Laser Specifications
IN
VIVO
STUDY
Kozarev, J., & Vižintin, Z. (2010) J Laser Health Academy, 1(1), 1–8
CONCLUSION:
Effective but…
Study lacks control group, (N=72)
The 1064 nm Nd:YAG laser was used with:
35-45 J/cm2 of fluence
30-35 msec of pulse duration
4 mm of spot size
1 Hz of frequency
32. • Same methodology and protocol
• Only 37.14% (N=35) negative cultures after 3
months
• Possible causes:
– 30% of patients had Scytalidium diminatum infection
– 14,3% of patients had dimished peripheral circulation
– Subungual hyperkeratosis?
FAILURE TO REPRODUCE
RESULTS
Wanitphakdeedecha R, The Efficacy and Safety of 1064 nm
Nd:YAG Laser in the Treatment of Onychomycosis – Thai Experiences
www.Fotona.com
IN
VIVO
STUDY
33. =
• 2 or 3 treatments
223 J/cm2 fluence,
2mm spot size
• Results:
– Negative cultures in 7/8
patients
• Conclusion:
– Non comparable results
– Small sample size
0.65 milisecond Nd:YAG 1064 nm
Hochman, L. G. (2011) Journal of cosmetic and laser therapy , 13(1), 2–5
IN
VIVO
STUDY
Laser: LightPod Neo, Aerolase
1 pass 2 pass ANTIFUNGAL
CREAM
34. Visible aiming beam
(coaxial with invisible treatment beam)
Visible working
distance beam
Invisible
Temperature
sensor
GenesisPlus (Cutera) Laser
Specifications
Two aiming beams + Temp Sensor
35. GenesisPlus (Cutera) Laser
Specifications
IN
VIVO
STUDY
The 1064 nm Nd:YAG laser was used with:
16 J/cm2 fluence
0,3 msec of pulse duration
5 mm of spot size
2 Hz of frequency
Goal for effective treatment is to heat and hold tissue temperature
at 43o- 46o as indicated by yellow LEDs
Use 700-800 pulses / 5 toes,
36. GenesisPlus (Cutera) Laser
Specifications
IN
VIVO
STUDY
Weiss D. 3 Month Clinical Results using Sub-millisecond
1064 nm Nd : YAG Laser for the Treatment of Onychomycosis.
CONCLUSION:
70% of improvment in nail condition
Study lacks control group, (N=7)
No cultures post Tx
The 1064 nm Nd:YAG laser was used with:
16 J/cm2 fluence
0,3 msec of pulse duration
5 mm of spot size
2 Hz of frequency
Results base on a subjective
score of a single examiner!!!
37. U. Kimura et al. study
IN
VIVO
STUDY
Kimura U, et al. J Drugs Dermatol. 2012 Apr;11(4):496-504
CONCLUSION:
Very similar design to previous study
51% of microscopicly negative samples
Study lacks control group, (N=13)
The 1064 nm Nd:YAG laser was used with:
14 J/cm2 fluence
0,3 msec of pulse duration
5 mm of spot size
5 Hz of frequency
38. Questions
Review of evidence
• Is there a need for laser treatment ?
• Is it effective ?
• Is it proven ?
• Which parameters ?
• Is it economically reasonable ?
39. Nail Anatomy and Types of Onychomycosis
Need to be defined in order to find the best technology
40. Light Absorption in Tissue makes a difference
1 µm
10 µm
100 µm
1 mm
10 mm
100 mm
1 m
10 m
100 m
0.1 0.5 1 2 30.40.30.2
1064 Nd:YAG
Water
Wavelength
Hemoglobin
Melanin
1320 nm Nd:YAG
1320 nm is
absorbed
uniformly in
water and tissue
with little effect
from melanin or
hemoglobin
41. 1 µm
10 µm
100 µm
1 mm
10 mm
100 mm
1 m
10 m
100 m
0.1 0.5 1 2 30.40.30.2
1064 nm Nd:YAG
Water
Wavelength
Hemoglobin
Melanin
1064 nm is not as
well absorbed in
water and tissue
Melanin or
hemoglobin are
the dominate
chromophores
Light Absorption in Tissue makes a
difference
42. Summary and discussion
• Studies proove positive effects
• Are hard to compare
• Small sample sizes
• Most had no control group
• Some were not reproducible
• Remissions: no comment
43. Questions
• Is there a need for laser treatment ?
• Is it effective ?
• Is it proven ?
• Which parameters ?
• Is it economically reasonable ?
Review of evidence
44. Is it economically reasonable ?
• Not reimbursed
• If effective 30-100 €/session
• Cost of device should not exceed 4 sessions in
100 patients = < 20 000 €
• Better : use an existing laser and adapt
similar parameters for addititional pay off
45. What’s next
• Photodynamic phototherapy?
• A standardized reasearch protocol
• Chromophore related laser treatment
• More studies on laser can be expected to
find best wavelenghth and protocol
• Studies OCT controlled?